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Wang X, Liu Q, Cheng P, Yang T, Zhao T, Liu M, Dai E, Sha W, Yuan J, Rong J, Qu H, Zhou H. LuQi formula ameliorates pressure overload-induced heart failure by regulating macrophages and regulatory T cells. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 141:156527. [PMID: 40118747 DOI: 10.1016/j.phymed.2025.156527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 02/11/2025] [Accepted: 02/15/2025] [Indexed: 03/23/2025]
Abstract
BACKGROUND Inflammatory macrophages in failing myocardium secrete CCL17, which targets CCR4 in immunosuppressive Tregs and inhibits the intracellular second messenger ARRB2-mediated cardiac chemotaxis. Traditional Chinese medicine (TCM) LuQi formula (LQF) is safe and effective in treating heart failure (HF). This study aims to elucidate the cardioprotective mechanism of LQF through its modulation of cardiac macrophages and Tregs. METHODS In vivo, the HF mouse model was established via transverse aortic constriction (TAC), with the superagonistic anti-CD28 monoclonal antibody (CD28-SA)-induced Tregs expansion as a positive control. Proteomics analysis elucidated the core link of LQF in anti-HF. In vitro, bone marrow-derived macrophages (BMDMs) were isolated, and Naive CD4+T cells were sorted and stimulated to differentiate into Tregs. The pharmacological mechanism of LQF was confirmed through histological and molecular biology experiments. RESULTS Proteomics reveals that LQF modulates the immune microenvironment of failing myocardium. We revealed that LQF inhibited cardiac inflammatory macrophage infiltration and NF-κB (p50, p65)/CCL17 axis expression, and promoted cardiac Tregs recruitment against HF, with the comparable efficacy of CD-SA28-induced Tregs expansion. Mechanistically, LQF inhibited the NF-κB activator 1-induced NF-κB (p50, p65)/CCL17 axis overexpression, and JSH-23 (NF-κB Inhibitor) abolished NF-κB (p50, p65)/CCL17 axis expression in inflammatory macrophages. Furthermore, the inhibition of CCL17 expression in inflammatory macrophages by LQF was found to be mediated by NF-κB (p50, p65). LQF concentration-dependently promoted Tregs CD73/Foxp3 axis expression, enhancing Tregs immunosuppressive function. LQF activated CCR4-ARRB2 complex and CCR4/ARRB2 axis expression in Tregs. Although AZD2098 (CCR4 Inhibitor) blocked CCR4 expression and CCR4-ARRB2 complex, LQF promoted ARRB2-mediated Tregs cardiac chemotaxis independent of the CCR4. We revealed that NF-κB p50SEP337-CCL17, NF-κB p65SEP536-CCL17, and CCR4-ARRB2 highly bound subunit interface targets. Molecular docking analysis demonstrated that the LQF's active ingredients exhibit good binding affinity with the NF-κB (p50, p65) /CCL17 axis in macrophages and Foxp3 in Tregs. CONCLUSION LQF has the potential to enhance the cardiac immune microenvironment and effectively prevent and treat HF by modulating both innate and adaptive immune responses. It achieves this by inhibiting the infiltration of inflammatory macrophages, suppressing the NF-κB (p50, p65)/CCL17 axis, and promoting Tregs recruitment. The active ingredients of LQF provide valuable candidate compounds for developing new anti-HF drugs. Furthermore, CD-28SA-induced Tregs expansion showed cardioprotective effects in TAC-induced non-ischemic HF models.
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Affiliation(s)
- Xinting Wang
- Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Qian Liu
- Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Peipei Cheng
- Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Tianshu Yang
- Department of Cardiovascular Disease, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, ShangHai 200040, China
| | - Tingyao Zhao
- Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200050, China
| | - Meng Liu
- Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200050, China
| | - Enrui Dai
- Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wanjing Sha
- Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jinfeng Yuan
- Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jingfeng Rong
- Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Huiyan Qu
- Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hua Zhou
- Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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Bozward AG, Davies SP, Morris SM, Kayani K, Oo YH. Cellular interactions in self-directed immune-mediated liver diseases. J Hepatol 2025; 82:1110-1124. [PMID: 39793614 DOI: 10.1016/j.jhep.2025.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 12/18/2024] [Accepted: 01/06/2025] [Indexed: 01/13/2025]
Abstract
The lymphocyte population must traverse a complex path throughout their journey to the liver. The signals which these cells must detect, including cytokines, chemokines and other soluble factors, steer their course towards further crosstalk with other hepatic immune cells, hepatocytes and biliary epithelial cells. A series of specific chemokine receptors and adhesion molecules drive not only the recruitment, migration, and retention of these cells within the liver, but also their localisation. Perturbation of these interactions and failure of self-recognition drive the development of several autoimmune liver diseases. We also describe check point-induced liver injury. Immune cell internalisation into hepatocytes (emperipolesis) in autoimmune hepatitis and into biliary epithelial cells (intra-epithelial lymphocyte) in primary biliary cholangitis are typical features in autoimmune liver diseases. Finally, we describe emerging immune-based therapies, including regulatory T cell, anti-cytokine and anti-chemokine therapies, cytokine supplementation (e.g. interleukin-2), as well as co-inhibitory molecule manipulation, including T-cell engagers, and discuss their potential application in the treatment of autoimmune liver diseases.
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Affiliation(s)
- Amber G Bozward
- Centre for Liver and Gastroenterology research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK; National Institute of Health Research Biomedical Research Centre, University of Birmingham and University Hospital Birmingham NHS Foundation Trust, Birmingham, UK; Centre for Rare Diseases, European Reference Network on Hepatological Diseases (ERN-RARE-LIVER) Centre, University of Birmingham, Birmingham, UK.
| | - Scott P Davies
- Centre for Liver and Gastroenterology research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK; National Institute of Health Research Biomedical Research Centre, University of Birmingham and University Hospital Birmingham NHS Foundation Trust, Birmingham, UK; Centre for Rare Diseases, European Reference Network on Hepatological Diseases (ERN-RARE-LIVER) Centre, University of Birmingham, Birmingham, UK
| | - Sean M Morris
- Centre for Liver and Gastroenterology research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK; National Institute of Health Research Biomedical Research Centre, University of Birmingham and University Hospital Birmingham NHS Foundation Trust, Birmingham, UK; Centre for Rare Diseases, European Reference Network on Hepatological Diseases (ERN-RARE-LIVER) Centre, University of Birmingham, Birmingham, UK
| | - Kayani Kayani
- Centre for Liver and Gastroenterology research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK; National Institute of Health Research Biomedical Research Centre, University of Birmingham and University Hospital Birmingham NHS Foundation Trust, Birmingham, UK; Centre for Rare Diseases, European Reference Network on Hepatological Diseases (ERN-RARE-LIVER) Centre, University of Birmingham, Birmingham, UK
| | - Ye H Oo
- Centre for Liver and Gastroenterology research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK; National Institute of Health Research Biomedical Research Centre, University of Birmingham and University Hospital Birmingham NHS Foundation Trust, Birmingham, UK; Centre for Rare Diseases, European Reference Network on Hepatological Diseases (ERN-RARE-LIVER) Centre, University of Birmingham, Birmingham, UK; Liver Transplant and Hepatobiliary Department, Queen Elizabeth Hospital, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK.
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3
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Yang L, Zheng SG. Role of regulatory T cells in inflammatory liver diseases. Autoimmun Rev 2025; 24:103806. [PMID: 40139456 DOI: 10.1016/j.autrev.2025.103806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 03/21/2025] [Accepted: 03/21/2025] [Indexed: 03/29/2025]
Abstract
The liver is the human body's largest digestive gland, which can participate in digestion, metabolism, excretion, detoxification and immunity. Chronic liver diseases such as metabolic dysfunction-associated fatty liver disease (MAFLD) or viral hepatitis involve ongoing inflammation and resulting liver fibrosis may ultimately lead to the development of hepatobiliary cancers (HCC). Inflammation is the coordinated reaction of different liver cell types to cell signals and death of inflammation, which are linked to injury pathways within the liver or external agents from the gut-liver axis and the circulation. Regulatory T (Treg) cells play a crucial role in controlling inflammation and are essential for maintaining immune tolerance and balance. In this review, we highlight the recent discoveries related to the function of immune systems in liver inflammation and discuss the role of Treg cells in the different liver diseases (including MAFLD, autoimmune hepatitis and others).
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Affiliation(s)
- Linjie Yang
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523808, China
| | - Song Guo Zheng
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523808, China; Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Songjiang District Central Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China; State Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, 201600, China.
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Suzuki K, Rao A, Onodera A. The TET-TDG axis in T cells and biological processes. Int Immunol 2025; 37:299-312. [PMID: 39921704 PMCID: PMC12096163 DOI: 10.1093/intimm/dxaf006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 02/06/2025] [Indexed: 02/10/2025] Open
Abstract
Ten-eleven translocation (TET) proteins are dioxygenases that sequentially oxidize the methyl group of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). All three epigenetic modifications are intermediates in DNA demethylation. In the "passive" (replication-dependent) DNA demethylation pathway, sequential oxidation reactions by TETs are essential and modified cytosines (C) are diluted at each cycle of DNA replication. In the "active" (replication-independent) DNA demethylation pathway, both thymine DNA glycosylase (TDG) and TETs play important roles. TDG removes 5fC and 5caC from 5fC:G and 5caC:G base pairs and these modified bases are replaced by unmodified C via base excision repair. Through epigenetic regulation of DNA demethylation, TETs and TDG are involved in cell development, differentiation, and homeostasis. The interplay between TDG and TETs is involved in embryo development, stem cell differentiation, neural development, immune responses, and tumorigenesis. Loss-of-function mutations of TET proteins in immune cells are associated with a variety of abnormalities, including inflammation, cancer, and clonal hematopoiesis, a condition related to aging. Loss of TETs also has a significant impact on the plasticity and differentiation of T cells, which contributes to inflammation and cancer. In this review, we describe recent findings in functions of TETs in T cell plasticity and differentiation and the TET-TDG axis in selected biological processes.
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Affiliation(s)
- Kazumasa Suzuki
- La Jolla Institute for Immunology, Center for Autoimmunity and Inflammation, La Jolla, CA 92037, USA
| | - Anjana Rao
- La Jolla Institute for Immunology, Center for Autoimmunity and Inflammation, La Jolla, CA 92037, USA
- Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA
- Moores Cancer Center, UC San Diego, La Jolla, CA 92037, USA
- Program in Immunology, UC San Diego, La Jolla, CA 92093, USA
- Department of Pharmacology, UC San Diego, La Jolla, CA 92161, USA
| | - Atsushi Onodera
- Institute for Advanced Academic Research (IAAR), Chiba University, Chiba, 263-8522, Japan
- Research Institute of Disaster Medicine (RIDM), Chiba University, Chiba, 260-8670, Japan
- Center for Human Immunological Diseases and Therapy Development (cCHID), Chiba University, Chiba, 260-8670, Japan
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Bhattacharya S, Fernandez CJ, Kamrul-Hasan ABM, Pappachan JM. Monogenic diabetes: An evidence-based clinical approach. World J Diabetes 2025; 16:104787. [DOI: 10.4239/wjd.v16.i5.104787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 02/20/2025] [Accepted: 03/11/2025] [Indexed: 04/25/2025] Open
Abstract
Monogenic diabetes is a heterogeneous disorder characterized by hyperglycemia arising from defects in a single gene. Maturity-onset diabetes of the young (MODY) is the most common type with 14 subtypes, each linked to specific mutations affecting insulin synthesis, secretion and glucose regulation. Common traits across MODY subtypes include early-onset diabetes, a family history of autosomal dominant diabetes, lack of features of insulin resistance, and absent islet cell autoimmunity. Many cases are misdiagnosed as type 1 and type 2 diabetes mellitus. Biomarkers and scoring systems can help identify candidates for genetic testing. GCK-MODY, a common subtype, manifests as mild hyperglycemia and doesn’t require treatment except during pregnancy. In contrast, mutations in HNF4A, HNF1A, and HNF1B genes lead to progressive beta-cell failure and similar risks of complications as type 2 diabetes mellitus. Neonatal diabetes mellitus (NDM) is a rare form of monogenic diabetes that usually presents within the first six months. Half of the cases are lifelong, while others experience transient remission. Permanent NDM is most commonly due to activating mutations in genes encoding the adenosine triphosphate-sensitive potassium channel (KCNJ11 or ABCC8) and can be transitioned to sulfonylurea after confirmation of diagnosis. Thus, in many cases, monogenic diabetes offers an opportunity to provide precision treatment. The scope has broadened with next-generation sequencing (NGS) technologies, replacing older methods like Sanger sequencing. NGS can be for targeted gene panels, whole-exome sequencing (WES), or whole-genome sequencing. Targeted gene panels offer specific information efficiently, while WES provides comprehensive data but comes with bioinformatic challenges. The surge in testing has also led to an increase in variants of unknown significance (VUS). Deciding whether VUS is disease-causing or benign can be challenging. Computational models, functional studies, and clinical knowledge help to determine pathogenicity. Advances in genetic testing technologies offer hope for improved diagnosis and personalized treatment but also raise concerns about interpretation and ethics.
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Affiliation(s)
| | - Cornelius J Fernandez
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, Lincolnshire, United Kingdom
| | | | - Joseph M Pappachan
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, Greater Manchester, United Kingdom
- Department of Endocrinology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, India
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Sureka N, Zaheer S. Regulatory T Cells in Tumor Microenvironment: Therapeutic Approaches and Clinical Implications. Cell Biol Int 2025. [PMID: 40365758 DOI: 10.1002/cbin.70031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 04/19/2025] [Accepted: 04/24/2025] [Indexed: 05/15/2025]
Abstract
Regulatory T cells (Tregs), previously referred to as suppressor T cells, represent a distinct subset of CD4+ T cells that are uniquely specialized for immune suppression. They are characterized by the constitutive expression of the transcription factor FoxP3 in their nuclei, along with CD25 (the IL-2 receptor α-chain) and CTLA-4 on their cell surface. Tregs not only restrict natural killer cell-mediated cytotoxicity but also inhibit the proliferation of CD4+ and CD8+ T-cells and suppress interferon-γ secretion by immune cells, ultimately impairing an effective antitumor immune response. Treg cells are widely recognized as a significant barrier to the effectiveness of tumor immunotherapy in clinical settings. Extensive research has consistently shown that Treg cells play a pivotal role in facilitating tumor initiation and progression. Conversely, the depletion of Treg cells has been linked to a marked delay in tumor growth and development.
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Affiliation(s)
- Niti Sureka
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
| | - Sufian Zaheer
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
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7
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Leng F, Merino-Urteaga R, Wang X, Zhang W, Ha T, Hur S. Ultrastable and versatile multimeric ensembles of FoxP3 on microsatellites. Mol Cell 2025; 85:1509-1524.e7. [PMID: 40179879 DOI: 10.1016/j.molcel.2025.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 01/29/2025] [Accepted: 03/05/2025] [Indexed: 04/05/2025]
Abstract
Microsatellites are essential genomic components increasingly linked to transcriptional regulation. FoxP3, a transcription factor critical for regulatory T cell (Treg) development, recognizes TTTG repeat microsatellites by forming multimers along DNA. However, FoxP3 also binds a broader range of TnG repeats (n = 2-5), often at the edges of accessible chromatin regions. This raises questions about how FoxP3 adapts to sequence variability and the potential role of nucleosomes. Using cryoelectron microscopy and single-molecule analyses, we show that murine FoxP3 assembles into various distinct supramolecular structures, depending on DNA sequence. This structural plasticity enables FoxP3 to bridge 2-4 DNA duplexes, forming ultrastable structures that coordinate multiple genomic loci. Nucleosomes further facilitate FoxP3 assembly by inducing local DNA bending, creating a nucleus that recruits distal DNA elements through multiway bridging. Our findings thus reveal FoxP3's unusual ability to shapeshift to accommodate evolutionarily dynamic microsatellites and its potential to reinforce chromatin boundaries and three-dimensional genomic architecture.
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Affiliation(s)
- Fangwei Leng
- Howard Hughes Medical Institute and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Institute of Immunology, Chinese Institutes for Medical Research, Beijing 100069, China
| | - Raquel Merino-Urteaga
- Howard Hughes Medical Institute and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Xi Wang
- Howard Hughes Medical Institute and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
| | - Wenxiang Zhang
- Howard Hughes Medical Institute and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Shanghai Institute of Immunology, Shanghai Jiaotong University, Shanghai 200025, China
| | - Taekjip Ha
- Howard Hughes Medical Institute and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
| | - Sun Hur
- Howard Hughes Medical Institute and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
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8
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Roux H, Lantz O. [Role of CD4 T cells in the immune response]. Med Sci (Paris) 2025; 41:336-345. [PMID: 40293150 DOI: 10.1051/medsci/2025048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/30/2025] Open
Abstract
CD4 T cells orchestrate the immune response, facilitating cytotoxic and humoral responses while preventing the destruction of one's own tissues by more autoreactive T cells. However, unlike complete CD4 T cell deficiency, the apparent deficiency caused by mutations in the CD4 gene that prevent its expression does not result in severe combined immunodeficiency in humans. The absence of the CD4 molecule limits the number of clones selected in the thymus on the basis of major histocompatibility complex type II, but does not prevent the acquisition of the T helper lymphocyte program, allowing them to retain most of their effector capacity. This observation raises new questions about the function of CD4 T cells and, in particular, the intrinsic role of the CD4 molecule.
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Affiliation(s)
- Hugo Roux
- Institut Curie, Université Paris Sciences et Lettres, Inserm U932, Immunité et cancer, Paris, France
| | - Olivier Lantz
- Institut Curie, Université Paris Sciences et Lettres, Inserm U932, Immunité et cancer, Paris, France - Laboratoire d'immunologie clinique, Institut Curie, Paris, France - Centre d'investigation Clinique en Biothérapie Gustave-Roussy Institut Curie (CIC-BT1428) Institut Curie, Paris, France
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9
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Luo S, Larson JH, Blazar BR, Abdi R, Bromberg JS. Foxp3 +CD8 + regulatory T cells: bona fide Tregs with cytotoxic function. Trends Immunol 2025; 46:324-337. [PMID: 40113537 DOI: 10.1016/j.it.2025.02.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 02/14/2025] [Accepted: 02/18/2025] [Indexed: 03/22/2025]
Abstract
Various mammalian CD8+ T cell subsets with regulatory properties are either formed through a thymus-dependent mechanism or induced under various experimental protocols and referred to as CD8+ regulatory T cells (Tregs). CD8+ Tregs maintain distinct functions in the presence of CD4+ Tregs. This review focuses on the Foxp3+CD8+ Treg subset, which is typically extremely rare in unmanipulated mice and healthy humans under steady-state conditions. However, they can be induced and expanded for transplantation, autoimmune diseases, cancer, viral infections, and T cell receptor transgenic adoptive cell transfer models. Here, we summarize recent research progress related to this population, including the identification of phenotypic markers, induction determinants, and functional activities. Additionally, we discuss advances in manipulating Foxp3+CD8+ Tregs in autoimmunity and transplantation.
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Affiliation(s)
- Shunqun Luo
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201
| | - Jemma H Larson
- Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, MN 55455
| | - Bruce R Blazar
- Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, University of Minnesota Cancer Center, Minneapolis, MN 55455
| | - Reza Abdi
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
| | - Jonathan S Bromberg
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201.
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Bender MJ, Lucas CL. Decoding Immunobiology Through Genetic Errors of Immunity. Annu Rev Immunol 2025; 43:285-311. [PMID: 39952637 DOI: 10.1146/annurev-immunol-082323-124920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2025]
Abstract
Throughout biology, the pursuit of genotype-phenotype relationships has provided foundational knowledge upon which new concepts and hypotheses are built. Genetic perturbation, whether occurring naturally or in experimental settings, is the mainstay of mechanistic dissection in biological systems. The unbiased discovery of causal genetic lesions via forward genetics in patients who have a rare disease elucidates a particularly impactful set of genotype-phenotype relationships. Here, we review the field of genetic errors of immunity, often termed inborn errors of immunity (IEIs), in a framework aimed at highlighting the powerful real-world immunology insights provided collectively and individually by these (approximately) 500 disorders. By conceptualizing essential immune functions in a model of the adaptive arsenal of rapid defenses, we organize IEIs based on immune circuits in which sensors, relays, and executioners cooperate to carry out pathogen clearance functions in an effective yet regulated manner. We review and discuss findings from IEIs that not only reinforce known immunology concepts but also offer surprising phenotypes, prompting an opportunity to refine our understanding of immune system function.
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Affiliation(s)
- Mackenzie J Bender
- Department of Immunobiology, Yale University, New Haven, Connecticut, USA;
| | - Carrie L Lucas
- Department of Immunobiology, Yale University, New Haven, Connecticut, USA;
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Steger K, Fiegl H, Feroz B, Leitner K, Marth C, Hackl H, Zeimet AG. Differences in immunogenicity of TP53-mutated cancers with low tumor mutational burden (TMB) A study on TP53mut endometrial-, ovarian- and triple-negative breast cancer. Eur J Cancer 2025; 219:115320. [PMID: 39986022 DOI: 10.1016/j.ejca.2025.115320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 02/11/2025] [Accepted: 02/14/2025] [Indexed: 02/24/2025]
Abstract
PURPOSE To explore why in large phase III randomized clinical trials TP53-mutated (TP53mut) endometrial cancer (EC) was the only tumor showing survival benefit to immune checkpoint inhibitors (ICIs) added to chemotherapy when compared with other low TMB TP53mut cancers, such as high-grade serous ovarian (HGSOC) and triple-negative breast cancer (TNBC). EXPERIMENTAL DESIGN From 606 patients with one of the three mentioned cancers, "The Cancer Genome Atlas" data on clinical outcome, TMB and detailed composition of the tumor immune-microenvironment (TIME) (immune infiltrating cells, cytokines, and other immune-modulators) were compared using the Kruskal-Wallis test, followed by Pearson correlation. Prognostic value of studied variables was assessed by Kaplan-Meier and Cox-regression analyses. RESULTS TMB was very low in all three TP53mut entities, being lowest in EC (median: 1.27 Mut/Mb; p < 0.001). Interestingly, high TMB was significantly associated with improved clinical outcome in every entity, whereby best discrimination for PFS was found in EC (HR: 0.52). Compared to EC, immune-suppressing regulatory T-cells were higher in HGSOC and TNBC (p < 0.001) and M2-like macrophages higher in HGSOC (p < 0.001). In contrast, immune-activating mDCs were more prominent in EC than in HGSOC (p < 0.001). Differential modulator expression analyses revealed highest discrimination for the immune-inhibiting FOXP3, C1QA and XBP1, which all exhibited lower levels in EC compared with HGSOC and TNBC (p < 0.001). CONCLUSION Characteristics of TIME differ substantially among the assessed entities in terms that EC exhibits fewer immunosuppressive traits, expecting a higher likelihood for responding to ICIs, despite a very low TMB, whereas HGSOC and TNBC exhibit an immune hostile TIME.
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Affiliation(s)
- Katharina Steger
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria
| | - Heidelinde Fiegl
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria
| | - Barin Feroz
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria
| | - Katharina Leitner
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria
| | - Christian Marth
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria
| | - Hubert Hackl
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria.
| | - Alain G Zeimet
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria.
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Savagner F, Farge T, Karim Z, Aloulou M. Iron and energy metabolic interactions in Treg-mediated immune regulation. Front Immunol 2025; 16:1554028. [PMID: 40176804 PMCID: PMC11961939 DOI: 10.3389/fimmu.2025.1554028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 03/03/2025] [Indexed: 04/04/2025] Open
Abstract
Immunometabolism, the study of how metabolic processes influence immune cell function, has emerged as a critical field in understanding the regulation of immune tolerance and the pathological mechanisms underlying autoimmune diseases. Intracellular metabolic pathways not only provide the necessary energy for immune cell survival and activity but also shape the differentiation, phenotype, proliferation, and effector functions of immune cells. This is particularly evident in CD4+ Foxp3+ regulatory T cells (Treg), which are pivotal for maintaining immune homeostasis and preventing autoimmune reactions. Strong experimental evidence highlights the profound impact of metabolism on Treg. Their anti-inflammatory function and ability to suppress excessive immune responses depend on the integration of metabolic cues with their transcriptional and signaling networks. Iron metabolism and mitochondrial dynamics are among the key factors influencing Treg function. This review focuses on how iron and mitochondrial metabolism shape Treg biology and function.
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Affiliation(s)
- Frédérique Savagner
- Biochemistry Laboratory, University of Toulouse, Toulouse, France
- Inserm U1297, Institute of Metabolic and Cardiovascular Diseases (I2MC), Toulouse, France
- Biochemistry Laboratory, Genetic and Hormonal Department, Federative Institute of Biology, Academic Hospital, Toulouse, France
| | - Thomas Farge
- Biochemistry Laboratory, University of Toulouse, Toulouse, France
- Inserm U1297, Institute of Metabolic and Cardiovascular Diseases (I2MC), Toulouse, France
| | - Zoubida Karim
- INFINITy, Toulouse Institute for Infectious and Inflammatory Diseases, INSERM U1291, CNRS U5051, University of Toulouse, Toulouse, France
| | - Meryem Aloulou
- INFINITy, Toulouse Institute for Infectious and Inflammatory Diseases, INSERM U1291, CNRS U5051, University of Toulouse, Toulouse, France
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13
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Xu L, Shen T, Li Y, Wu X. The Role of M 6A Modification in Autoimmunity: Emerging Mechanisms and Therapeutic Implications. Clin Rev Allergy Immunol 2025; 68:29. [PMID: 40085180 DOI: 10.1007/s12016-025-09041-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/03/2025] [Indexed: 03/16/2025]
Abstract
N6-methyladenosine (m6A), a prevalent and essential RNA modification, serves a key function in driving autoimmune disease pathogenesis. By modulating immune cell development, activation, migration, and polarization, as well as inflammatory pathways, m6A is crucial in forming innate defenses and adaptive immunity. This article provides a comprehensive overview of m6A modification features and reveals how its dysregulation affects the intensity and persistence of immune responses, disrupts immune tolerance, exacerbates tissue damage, and promotes the development of autoimmunity. Specific examples include its contributions to systemic autoimmune disorders like lupus and rheumatoid arthritis, as well as conditions that targeting specific organs like multiple sclerosis and type 1 diabetes. Furthermore, this review explores the therapeutic promise of target m6A-related enzymes ("writers," "erasers," and "readers") and summarizes recent advances in intervention strategies. By focusing on the mechanistic and therapeutic implications of m6A modification, this review sheds light on its role as a promising tool for both diagnosis and treatment in autoimmune disorders, laying the foundation for advancements in customized medicine.
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Affiliation(s)
- Liyun Xu
- Department of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Tian Shen
- Department of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
| | - Yongzhen Li
- Department of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
| | - Xiaochuan Wu
- Department of Pediatrics, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
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14
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Engelhart MJ, Brock OD, Till JM, Glowacki RWP, Cantwell JW, Clarke DJ, Wesener DA, Ahern PP. BT1549 coordinates the in vitro IL-10 inducing activity of Bacteroides thetaiotaomicron. Microbiol Spectr 2025; 13:e0166924. [PMID: 39868786 PMCID: PMC11878027 DOI: 10.1128/spectrum.01669-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 11/27/2024] [Indexed: 01/28/2025] Open
Abstract
The intestine is home to a complex immune system that is engaged in mutualistic interactions with the microbiome that maintain intestinal homeostasis. A variety of immune-derived anti-inflammatory mediators have been uncovered and shown to be critical for maintaining these beneficial immune-microbiome relationships. Notably, the gut microbiome actively invokes the induction of anti-inflammatory pathways that limit the development of microbiome-targeted inflammatory immune responses. Despite the importance of this microbiome-driven immunomodulation, detailed knowledge of the microbial factors that promote these responses remains limited. We have previously established that the gut symbiont Bacteroides thetaiotaomicron stimulates the production of the anti-inflammatory cytokine IL-10 via soluble factors in a Toll-like receptor 2 (TLR2)-MyD88-dependent manner. Here, using TLR2 activity reporter cell lines, we show that the capacity of B. thetaiotaomicron to stimulate TLR2 activity was not critically dependent on either of the canonical heterodimeric forms of TLR2, TLR2/TLR1, or TLR2/TLR6, that typically mediate its function. Furthermore, biochemical manipulation of B. thetaiotaomicron-conditioned media suggests that IL-10 induction is mediated by a protease-resistant or non-proteogenic factor. We next uncovered that deletion of gene BT1549, a predicted secreted lipoprotein, significantly impaired the capacity of B. thetaiotaomicron to induce IL-10, while complementation in trans restored IL-10 induction, suggesting a role for BT1549 in the immunomodulatory function of B. thetaiotaomicron. Collectively, these data provide molecular insight into the pathways through which B. thetaiotaomicron operates to promote intestinal immune tolerance and symbiosis. IMPORTANCE Intestinal homeostasis requires the establishment of peaceful interactions between the gut microbiome and the intestinal immune system. Members of the gut microbiome, like the symbiont Bacteroides thetaiotaomicron, actively induce anti-inflammatory immune responses to maintain mutualistic relationships with the host. Despite the importance of such interactions, the specific microbial factors responsible remain largely unknown. Here, we show that B. thetaiotaomicron, which stimulates Toll-like receptor 2 (TLR2) to drive IL-10 production, can stimulate TLR2 independently of TLR1 or TLR6, the two known TLR that can form heterodimers with TLR2 to mediate TLR2-dependent responses. Furthermore, we show that IL-10 induction is likely mediated by a protease-resistant or non-proteogenic factor, and that this requires gene BT1549, a predicted secreted lipoprotein and peptidase. Collectively, our work provides insight into the molecular dialog through which B. thetaiotaomicron coordinates anti-inflammatory immune responses. This knowledge may facilitate future strategies to promote such responses for therapeutic purposes.
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Affiliation(s)
- Morgan J. Engelhart
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Orion D. Brock
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Jessica M. Till
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Robert W. P. Glowacki
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Jason W. Cantwell
- Department of Microbiology, The Ohio State University, Columbus, Ohio, USA
| | - David J. Clarke
- School of Microbiology and APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Darryl A. Wesener
- Department of Microbiology, The Ohio State University, Columbus, Ohio, USA
| | - Philip P. Ahern
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
- Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
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15
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Dikiy S, Ghelani AP, Levine AG, Martis S, Giovanelli P, Wang ZM, Beroshvili G, Pritykin Y, Krishna C, Huang X, Glasner A, Greenbaum BD, Leslie CS, Rudensky AY. Terminal differentiation and persistence of effector regulatory T cells essential for preventing intestinal inflammation. Nat Immunol 2025; 26:444-458. [PMID: 39905200 PMCID: PMC11876075 DOI: 10.1038/s41590-024-02075-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 12/30/2024] [Indexed: 02/06/2025]
Abstract
Regulatory T (Treg) cells are a specialized CD4+ T cell lineage with essential anti-inflammatory functions. Analysis of Treg cell adaptations to non-lymphoid tissues that enable their specialized immunosuppressive and tissue-supportive functions raises questions about the underlying mechanisms of these adaptations and whether they represent stable differentiation or reversible activation states. Here, we characterize distinct colonic effector Treg cell transcriptional programs. Attenuated T cell receptor (TCR) signaling and acquisition of substantial TCR-independent functionality seems to facilitate the terminal differentiation of a population of colonic effector Treg cells that are distinguished by stable expression of the immunomodulatory cytokine IL-10. Functional studies show that this subset of effector Treg cells, but not their expression of IL-10, is indispensable for colonic health. These findings identify core features of the terminal differentiation of effector Treg cells in non-lymphoid tissues and their function.
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Affiliation(s)
- Stanislav Dikiy
- Howard Hughes Medical Institute and Immunology Program, Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.
- Department of Immunology and Microbiology, Scripps Research, La Jolla, CA, USA.
| | - Aazam P Ghelani
- Howard Hughes Medical Institute and Immunology Program, Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA
| | - Andrew G Levine
- Howard Hughes Medical Institute and Immunology Program, Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Stephen Martis
- Computational Oncology, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Paolo Giovanelli
- Howard Hughes Medical Institute and Immunology Program, Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA
| | - Zhong-Min Wang
- Howard Hughes Medical Institute and Immunology Program, Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Giorgi Beroshvili
- Howard Hughes Medical Institute and Immunology Program, Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA
| | - Yuri Pritykin
- Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Lewis-Sigler Institute for Integrative Genomics and Department of Computer Science, Princeton University, Princeton, NJ, USA
| | - Chirag Krishna
- Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Xiao Huang
- Howard Hughes Medical Institute and Immunology Program, Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ariella Glasner
- Howard Hughes Medical Institute and Immunology Program, Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Benjamin D Greenbaum
- Computational Oncology, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Christina S Leslie
- Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Alexander Y Rudensky
- Howard Hughes Medical Institute and Immunology Program, Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.
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16
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Yuan Z, Liu M, Zhang L, Jia L, Hao S, Su D, Tang L, Wang C, Wang M, Wen Z. Notch1 hyperactivity drives ubiquitination of NOX2 and dysfunction of CD8+ regulatory T cells in patients with systemic lupus erythematosus. Rheumatology (Oxford) 2025; 64:1500-1512. [PMID: 38652598 DOI: 10.1093/rheumatology/keae231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 03/24/2024] [Accepted: 04/11/2024] [Indexed: 04/25/2024] Open
Abstract
OBJECTIVES Patients with SLE display heightened immune activation and elevated IgG autoantibody levels, indicating compromised regulatory T cell (Tregs) function. Our recent findings pinpoint CD8+ Tregs as crucial regulators within secondary lymphoid organs, operating in a NOX2-dependent mechanism. However, the specific involvement of CD8+ Tregs in SLE pathogenesis and the mechanisms underlying their role remain uncertain. METHODS SLE and healthy individuals were enlisted to assess the quantity and efficacy of Tregs. CD8+CD45RA+CCR7+ Tregs were generated ex vivo, and their suppressive capability was gauged by measuring pZAP70 levels in targeted T cells. Notch1 activity was evaluated by examining activated Notch1 and HES1, with manipulation of Notch1 accomplished with Notch inhibitor DAPT, Notch1 shRNA, and Notch1-ICD. To create humanized SLE chimaeras, immune-deficient NSG mice were engrafted with PBMCs from SLE patients. RESULTS We observed a reduced frequency and impaired functionality of CD8+ Tregs in SLE patients. There was a downregulation of NOX2 in CD8+ Tregs from SLE patients, leading to a dysfunction. Mechanistically, the reduction of NOX2 in SLE CD8+ Tregs occurred at a post-translational level rather than at the transcriptional level. SLE CD8+ Tregs exhibited heightened Notch1 activity, resulting in increased expression of STUB1, an E3 ubiquitin ligase that binds to NOX2 and facilitates its ubiquitination. Consequently, restoring NOX2 levels and inhibiting Notch1 activity could alleviate the severity of the disease in humanized SLE chimaeras. CONCLUSION Notch1 is the cell-intrinsic mechanism underlying NOX2 deficiency and CD8+ Treg dysfunction, serving as a therapeutic target for the clinical management of SLE.
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Affiliation(s)
- Zixin Yuan
- Jiangsu Key Laboratory of Infection and Immunity, The Fourth Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Suzhou Medical College of Soochow University, Soochow University, Suzhou, China
- MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Soochow University, Suzhou, China
| | - Mengdi Liu
- Jiangsu Key Laboratory of Infection and Immunity, The Fourth Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Suzhou Medical College of Soochow University, Soochow University, Suzhou, China
- MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Soochow University, Suzhou, China
| | - Lei Zhang
- Jiangsu Key Laboratory of Infection and Immunity, The Fourth Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Suzhou Medical College of Soochow University, Soochow University, Suzhou, China
- MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Soochow University, Suzhou, China
| | - Li Jia
- Jiangsu Key Laboratory of Infection and Immunity, The Fourth Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Suzhou Medical College of Soochow University, Soochow University, Suzhou, China
- MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Soochow University, Suzhou, China
| | - Siao Hao
- Jiangsu Key Laboratory of Infection and Immunity, The Fourth Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Suzhou Medical College of Soochow University, Soochow University, Suzhou, China
- MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Soochow University, Suzhou, China
| | - Danhua Su
- Jiangsu Key Laboratory of Infection and Immunity, The Fourth Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Suzhou Medical College of Soochow University, Soochow University, Suzhou, China
- MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Soochow University, Suzhou, China
| | - Longhai Tang
- Division of Research Center, Suzhou Blood Center, Suzhou, China
| | - Chunhong Wang
- Cyrus Tang Hematology Center, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China
| | - Mingyuan Wang
- Division of Research Center, Suzhou Blood Center, Suzhou, China
| | - Zhenke Wen
- Jiangsu Key Laboratory of Infection and Immunity, The Fourth Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Suzhou Medical College of Soochow University, Soochow University, Suzhou, China
- MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Soochow University, Suzhou, China
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17
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Lachota M, Zagożdżon R. Synthetic receptor-based cell therapies for autoimmune diseases: an update. Cytotherapy 2025:S1465-3249(25)00064-7. [PMID: 40117434 DOI: 10.1016/j.jcyt.2025.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 02/13/2025] [Accepted: 02/20/2025] [Indexed: 03/23/2025]
Abstract
Increasing frequency of autoimmune diseases is one of the major problems in modern societies. Despite the introduction of new therapeutic agents for autoimmunity over the past several decades, more progress is needed. Synthetic receptor-based cell therapies are being adopted as an option for treating autoimmune diseases from the field of oncology. Currently evaluated strategies can be summarized into two approaches. The first one is the elimination of autoreactive cells by targeting them, for example, with CAR-T or CAAR-T cells. The second is based on rebalancing the proinflammatory milieu with engineered immunosuppressive cells, for example, CAR-Treg. Both approaches can be supplemented with the use of synthetic systems such as Split-CAR, SynNotch, MESA, GEMS, and SNIPR, or prospective off-the-shelf approaches, for example, in situ use of the in vitro transcribed mRNA, ultimately allowing for enhanced efficacy and safety. The primary goal of our review is to provide some perspective on both strategies in basic, translational, and clinical studies with all their advantages and disadvantages to allow for informed future design of adoptive cell therapies for autoimmune diseases.
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Affiliation(s)
- Mieszko Lachota
- Laboratory of Cellular and Genetic Therapies, Medical University of Warsaw, Warsaw, Poland; Department of Ophthalmology, Children's Memorial Health Institute, Warsaw, Poland
| | - Radosław Zagożdżon
- Laboratory of Cellular and Genetic Therapies, Medical University of Warsaw, Warsaw, Poland.
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18
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Akbarialiabad H, Schmidt E, Patsatsi A, Lim YL, Mosam A, Tasanen K, Yamagami J, Daneshpazhooh M, De D, Cardones ARG, Joly P, Murrell DF. Bullous pemphigoid. Nat Rev Dis Primers 2025; 11:12. [PMID: 39979318 DOI: 10.1038/s41572-025-00595-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/14/2025] [Indexed: 02/22/2025]
Abstract
Bullous pemphigoid is a chronic, subepidermal autoimmune blistering disease characterized by tense blisters on erythematous or normal skin that predominantly affects the older population. The disease arises from autoantibodies targeting hemidesmosomal proteins BP180 and BP230, which are crucial for dermal-epidermal adhesion. The incidence of bullous pemphigoid is increasing, attributed to an ageing population and improved diagnostic recognition. Genetic predisposition, environmental triggers and associations with other autoimmune disorders underline its multifactorial nature. Diagnosis involves clinical presentation, histopathology, direct immunofluorescence and serological tests. Treatment aims to reduce symptoms and prevent new blister formation, using corticosteroids, immunosuppressive agents and biologics such as rituximab and omalizumab. Despite therapeutic advancements, challenges persist in long-term management, especially in older patients with comorbidities. Ongoing research into molecular mechanisms and novel therapeutic targets and clinical trials are crucial for the development of safer and more effective treatments.
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Affiliation(s)
- Hossein Akbarialiabad
- Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
- Australasian Blistering Diseases Foundation (ABDF), Sydney, New South Wales, Australia
| | - Enno Schmidt
- Department of Dermatology and Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany
| | - Aikaterini Patsatsi
- Center of Expertise on AIBD, 2nd Dermatology Department, Aristotle University School of Medicine, Papageorgiou General Hospital, Thessaloniki, Greece
| | - Yen Loo Lim
- National Skin Centre, Singapore, Singapore
- Yong Loo Lin School of Medicine, Singapore, Singapore
- Lee Kong Chian School of Medicine, Singapore, Singapore
| | - Anisa Mosam
- Department of Dermatology, Inkosi Albert Luthuli Central Hospital and Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
| | - Kaisa Tasanen
- Department of Dermatology and Medical Research Center Oulu, Oulu University Hospital, Oulu, Finland
- Research Unit of Clinical Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland
| | - Jun Yamagami
- Department of Dermatology, Tokyo Women's Medical University, Tokyo, Japan
| | - Maryam Daneshpazhooh
- Autoimmune Bullous Diseases Research Center, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Dipankar De
- Department of Dermatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Adela Rambi G Cardones
- Division of Dermatology, Department of Internal Medicine, University of Kansas Medical Center, Lawrence, KS, USA
| | - Pascal Joly
- Dermatology Department, Rouen University Hospital, INSERM U1234, Normandie University, Rouen, France.
| | - Dedee F Murrell
- Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
- Australasian Blistering Diseases Foundation (ABDF), Sydney, New South Wales, Australia.
- Department of Dermatology, St George Hospital, Sydney, New South Wales, Australia.
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19
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Clemons RA, Smith CH, Zamudio KR. Primary regulatory T cell activator FOXP3 is present across Amphibia. Immunogenetics 2025; 77:15. [PMID: 39945843 DOI: 10.1007/s00251-025-01372-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 02/05/2025] [Indexed: 05/09/2025]
Abstract
The overall structure of the immune system is highly conserved across jawed vertebrates, but characterization and description of the immune system is heavily biased toward mammals. One arm of the vertebrate immune system, the adaptive immune system, mounts pathogen-specific responses that tend to be robust and effective at clearing pathogens. This system requires selection against self-recognition and modulation of the immune response. One of the mechanisms of immune modulation is the presence of regulatory T cells that suppress other effector immune cells. Regulatory T cells and their primary activator forkhead box protein P3 (FOXP3) have been well characterized in mammalian models but unexplored in most other vertebrate taxa. Amphibians are a good focal group for the characterization of FOXP3 due to their phylogenetic position on the vertebrate tree of life, and their susceptibility to emerging pathogens. In this study, we mined available transcriptomic and genomic data to confirm the presence of FOXP3 across the amphibian tree of life. We find that FOXP3 is present in all major clades of amphibians. We also test whether selection on FOXP3 shows signatures of intensification among the three main clades of amphibians, which may reflect shifts in the stringency of natural selection on this gene. Our findings provide insights into the evolutionary history of the vertebrate immune system and confirm the conservation of vertebrate immune genes within amphibians.
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Affiliation(s)
- Rebecca A Clemons
- Department of Integrative Biology, The University of Texas at Austin, Austin, TX, USA.
| | - Chase H Smith
- Department of Integrative Biology, The University of Texas at Austin, Austin, TX, USA
| | - Kelly R Zamudio
- Department of Integrative Biology, The University of Texas at Austin, Austin, TX, USA
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20
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Wardell CM, Boardman DA, Levings MK. Harnessing the biology of regulatory T cells to treat disease. Nat Rev Drug Discov 2025; 24:93-111. [PMID: 39681737 DOI: 10.1038/s41573-024-01089-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/25/2024] [Indexed: 12/18/2024]
Abstract
Regulatory T (Treg) cells are a suppressive subset of CD4+ T cells that maintain immune homeostasis and restrain inflammation. Three decades after their discovery, the promise of strategies to harness Treg cells for therapy has never been stronger. Multiple clinical trials seeking to enhance endogenous Treg cells or deliver them as a cell-based therapy have been performed and hint at signs of success, as well as to important limitations and unanswered questions. Strategies to deplete Treg cells in cancer are also in active clinical testing. Furthermore, multi-dimensional methods to interrogate the biology of Treg cells are leading to a refined understanding of Treg cell biology and new approaches to harness tissue-specific functions for therapy. A new generation of Treg cell clinical trials is now being fuelled by advances in nanomedicine and synthetic biology, seeking more precise ways to tailor Treg cell function. This Review will discuss recent advances in our understanding of human Treg cell biology, with a focus on mechanisms of action and strategies to assess outcomes of Treg cell-targeted therapies. It highlights results from recent clinical trials aiming to enhance or inhibit Treg cell activity in a variety of diseases, including allergy, transplantation, autoimmunity and cancer, and discusses ongoing strategies to refine these approaches.
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Affiliation(s)
- Christine M Wardell
- BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
- Department of Surgery, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Dominic A Boardman
- BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
- Department of Surgery, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Megan K Levings
- BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.
- Department of Surgery, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
- School of Biomedical Engineering, University of British Columbia, Vancouver, British Columbia, Canada.
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21
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Wang A, Wang Y, Liang R, Li B, Pan F. Improving regulatory T cell-based therapy: insights into post-translational modification regulation. J Genet Genomics 2025; 52:145-156. [PMID: 39357622 DOI: 10.1016/j.jgg.2024.09.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 09/23/2024] [Accepted: 09/24/2024] [Indexed: 10/04/2024]
Abstract
Regulatory T (Treg) cells are pivotal for maintaining immune homeostasis and play essential roles in various diseases, such as autoimmune diseases, graft-versus-host disease (GVHD), tumors, and infectious diseases. Treg cells exert suppressive function via distinct mechanisms, including inhibitory cytokines, granzyme or perforin-mediated cytolysis, metabolic disruption, and suppression of dendritic cells. Forkhead Box P3 (FOXP3), the characteristic transcription factor, is essential for Treg cell function and plasticity. Cumulative evidence has demonstrated that FOXP3 activity and Treg cell function are modulated by a variety of post-translational modifications (PTMs), including ubiquitination, acetylation, phosphorylation, methylation, glycosylation, poly(ADP-ribosyl)ation, and uncharacterized modifications. This review describes Treg cell suppressive mechanisms and summarizes the current evidence on PTM regulation of FOXP3 and Treg cell function. Understanding the regulatory role of PTMs in Treg cell plasticity and function will be helpful in designing therapeutic strategies for autoimmune diseases, GVHD, tumors, and infectious diseases.
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Affiliation(s)
- Aiting Wang
- Center for Cancer Immunology Research, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China.
| | - Yanwen Wang
- Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Rui Liang
- Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Bin Li
- Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Fan Pan
- Center for Cancer Immunology Research, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China.
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22
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Zhang X, Zhang B, Li D, Yang Y, Lin S, Zhao R, Li Y, Peng L. Peripheral blood cell counts as predictors of immune-related adverse events in cancer patients receiving immune checkpoint inhibitors: a systematic review and meta-analysis. Front Immunol 2025; 16:1528084. [PMID: 39949762 PMCID: PMC11821924 DOI: 10.3389/fimmu.2025.1528084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 01/13/2025] [Indexed: 02/16/2025] Open
Abstract
Background In recent years, immune checkpoint inhibitors (ICIs) have shown significant efficacy in treating various malignancies and have become a key therapeutic approach in cancer treatment. However, while ICIs activate the immune system, they can also induce immune-related adverse events (irAEs). Due to the variability in the frequency and severity of irAEs, clinical management faces a significant challenge in balancing antitumor efficacy with the risk of irAEs. Predicting and preventing irAEs during the early stages of treatment has become a critical research focus in cancer immunotherapy. This study aims to evaluate the predictive value of peripheral blood cell counts for irAEs. Methods Studies meeting the inclusion criteria were identified through database searches. The standardized mean difference (SMD) was used to compare continuous blood cell counts. For studies that did not provide adjusted odds ratios (ORs) and 95% confidence intervals (CIs), crude ORs for categorized blood cell counts were calculated. The study protocol was registered on PROSPERO (CRD42024592126). Results The meta-analysis included 60 studies involving 16,736 cancer patients treated with ICIs. Compared to patients without irAEs, those experiencing irAEs had significantly higher baseline continuous ALC (SMD = 0.12, 95% CI = 0.01-0.24), while ANC (SMD = -0.18, 95% CI = -0.28 to -0.07) and PLR (SMD = -0.32, 95% CI = -0.60 to -0.04) were significantly lower. Similarly, categorized blood cell counts indicated that higher baseline ALC (OR = 2.46, 95% CI = 1.69-3.57) and AEC (OR = 2.05, 95% CI = 1.09-3.85), along with lower baseline NLR (OR = 0.64, 95% CI = 0.50-0.81) and PLR (OR = 0.63, 95% CI = 0.48-0.82), were associated with an increased risk of irAEs. Subgroup analysis further identified cutoff values for ALC (2×10^9/L), NLR (5 or 3), and PLR (180) as better predictors of irAEs. Conclusion Higher baseline ALC and AEC, along with lower baseline ANC, NLR, and PLR, are associated with an increased risk of irAEs. However, further research is needed to determine the optimal cutoff values and to explore the efficacy of blood cell counts in predicting specific types of irAEs. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024592126.
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Affiliation(s)
- Xinyu Zhang
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Bei Zhang
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Danfei Li
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Yunchao Yang
- Shandong College of Traditional Chinese Medicine, Shandong, Yantai, China
| | - Sen Lin
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Ruiqi Zhao
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Yijia Li
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China
| | - Lisheng Peng
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
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23
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Okeugo B, Armbrister SA, Daniel RC, Saleh ZM, Wang J, Giorgberidze S, Rhoads JM, Liu Y. Reduced autoimmunity associated with deletion of host CD73. Immunohorizons 2025; 9:vlae004. [PMID: 39846845 PMCID: PMC11841978 DOI: 10.1093/immhor/vlae004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 10/24/2024] [Indexed: 01/24/2025] Open
Abstract
CD73 is ubiquitously expressed and regulates critical functions across multiple organ systems. The sequential actions of CD39 and CD73 accomplish the conversion of adenosine triphosphate to adenosine and shift the adenosine triphosphate-driven proinflammatory immune cell milieu toward an anti-inflammatory state. This immunological switch is a major mechanism by which regulatory T (Treg) cells control inflammation. Foxp3 engages in Treg development and function. Foxp3 mutations result in the scurfy (SF) mouse phenotype and a rapidly lethal lymphoproliferative syndrome. We generated double knockout (KO) mouse (CD73KOSF) by breeding heterozygous Foxp3sf/J females to CD73KO male mice to remove host CD73. We initially aimed to use these mice to identify a specific probiotic-CD73 effect, previously shown for Limosilactobacillus reuteri DSM 17938. We expected CD73 deletion to enhance the severity of autoimmunity in SF mice. However, we unexpectedly observed that KO of host CD73 in SF mice clinically reduced the severity of autoimmunity including reduced ear thickness, increased ear size, and less deformed ears, along with less dry and brittle skin. KO of CD73 in SF mice significantly reduced the numbers of CD4+ and CD8+T cells in spleen and blood. We identified that KO of CD73 in SF mice reduced the numbers of T cells in the thymus compared with those in SF mice, indicating that the milder clinical phenotype may be due to reduced central and peripheral lymphoproliferation. These new findings suggest targeting CD73 could improve T cell-mediated dermatitis, one of the most common symptoms in Treg deficiency-associated primary immune deficiencies.
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Affiliation(s)
- Beanna Okeugo
- Department of Pediatrics, Division of Gastroenterology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Shabba A Armbrister
- Department of Pediatrics, Division of Gastroenterology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Rhea C Daniel
- Department of Pediatrics, Division of Gastroenterology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Zeina M Saleh
- Department of Pediatrics, Division of Gastroenterology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Jessica Wang
- Department of Pediatrics, Division of Gastroenterology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Salomea Giorgberidze
- Department of Pediatrics, Division of Gastroenterology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - J Marc Rhoads
- Department of Pediatrics, Division of Gastroenterology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Yuying Liu
- Department of Pediatrics, Division of Gastroenterology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
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24
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Noguerol J, Laviolette K, Zahm M, Chaubet A, Sahal A, Détraves C, Torres R, Demont C, Adoue V, Joffre C, Cammas F, van Meerwijk JP, Joffre OP. Heterochromatic gene silencing controls CD4 + T cell susceptibility to regulatory T cell-mediated suppression in a murine allograft model. Nat Commun 2025; 16:566. [PMID: 39794349 PMCID: PMC11723947 DOI: 10.1038/s41467-025-55848-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 01/02/2025] [Indexed: 01/13/2025] Open
Abstract
Protective immune responses require close interactions between conventional (Tconv) and regulatory T cells (Treg). The extracellular mediators and signaling events that regulate the crosstalk between these CD4+ T cell subsets have been extensively characterized. However, how Tconv translate Treg-dependent suppressive signals at the chromatin level remains largely unknown. Here we show, using a murine bone marrow allograft model in which graft rejection is coordinated by CD4+ T cells and can be inhibited by Treg, that Treg-mediated T cell suppression involves Heterochromatin Protein 1 α (HP1α)-dependent gene silencing. Unexpectedly, our screen also reveals that T cells deficient for HP1γ or the methyltransferase SUV39H1 are better repressed by Treg than their wild-type counterparts. Mechanistically, our transcriptional and epigenetic profiling identifies HP1γ as a negative regulator of a gene network functionally associated with T-cell exhaustion, including those encoding the inhibitory receptors PD-1 and LAG-3. In conclusion, we identify HP1 variants as rheostats that finely tune the balance between tolerance and immunity. While HP1α converts immunosuppressive signals into heterochromatin-dependent gene silencing mechanisms, HP1γ adjusts Tconv sensitivity to inhibitory environmental signals.
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Affiliation(s)
- Julie Noguerol
- Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291, CNRS U5051, Toulouse, France
| | - Karl Laviolette
- Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291, CNRS U5051, Toulouse, France
| | - Margot Zahm
- Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291, CNRS U5051, Toulouse, France
| | - Adeline Chaubet
- Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291, CNRS U5051, Toulouse, France
| | - Ambrine Sahal
- Centre de Recherche en Cancérologie de Toulouse, Université de Toulouse, Inserm U1037, CNRS U5071, Toulouse, France
| | - Claire Détraves
- Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291, CNRS U5051, Toulouse, France
| | - Romain Torres
- Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291, CNRS U5051, Toulouse, France
| | - Clothilde Demont
- Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291, CNRS U5051, Toulouse, France
| | - Véronique Adoue
- Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291, CNRS U5051, Toulouse, France
| | - Carine Joffre
- Centre de Recherche en Cancérologie de Toulouse, Université de Toulouse, Inserm U1037, CNRS U5071, Toulouse, France
| | - Florence Cammas
- Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université Montpellier, 34298, Montpellier, France
- Institut Régional du Cancer Montpellier, Université Montpellier, 34298, Montpellier, France
- Institute of Human Genetics, CNRS UMR9002 University of Montpellier, 34396, Montpellier, France
| | - Joost Pm van Meerwijk
- Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291, CNRS U5051, Toulouse, France
| | - Olivier P Joffre
- Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291, CNRS U5051, Toulouse, France.
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25
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Lee KY, Mei Y, Liu H, Schwarz H. CD137-expressing regulatory T cells in cancer and autoimmune diseases. Mol Ther 2025; 33:51-70. [PMID: 39668561 PMCID: PMC11764688 DOI: 10.1016/j.ymthe.2024.12.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 11/25/2024] [Accepted: 12/06/2024] [Indexed: 12/14/2024] Open
Abstract
Regulatory T cells (Tregs) are essential for maintaining immune homeostasis, with critical roles in preventing aberrant immune responses that occur in autoimmune diseases and chronic inflammation. Conversely, the abundance of Tregs in cancer is associated with impaired anti-tumor immunity, and tumor immune evasion. Recent work demonstrates that CD137, a well-known costimulatory molecule for T cells, is highly expressed on Tregs in pathological conditions, while its expression is minimal or negligible on peripheral Tregs. The expression of CD137 marks Tregs with potent immunosuppressive phenotype that foster cancer progression and are protective against certain autoimmune diseases. Hence CD137 has emerged as a marker for Tregs. However, several important questions still remain regarding the expression and function of CD137 in Tregs. Here, we provide an overview of our current knowledge of Treg mechanisms of action, with a focus on the role of CD137 in modulating Treg activity. We also explore the implications of CD137+ Tregs in both cancer and autoimmune diseases, emphasizing the significance of targeting these cells for therapeutic intervention in these conditions.
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Affiliation(s)
- Kang Yi Lee
- NUS Immunology Programme, Life Sciences Institute, Department of Microbiology and Immunology, National University of Singapore, Singapore 117545, Singapore; NUSMED Immunology Translational Research Programme, National University of Singapore, Singapore 117456, Singapore
| | - Yu Mei
- NUS Immunology Programme, Life Sciences Institute, Department of Microbiology and Immunology, National University of Singapore, Singapore 117545, Singapore; NUSMED Immunology Translational Research Programme, National University of Singapore, Singapore 117456, Singapore
| | - Haiyan Liu
- NUS Immunology Programme, Life Sciences Institute, Department of Microbiology and Immunology, National University of Singapore, Singapore 117545, Singapore; NUSMED Immunology Translational Research Programme, National University of Singapore, Singapore 117456, Singapore.
| | - Herbert Schwarz
- NUS Immunology Programme, Life Sciences Institute, Department of Microbiology and Immunology, National University of Singapore, Singapore 117545, Singapore; NUSMED Immunology Translational Research Programme, National University of Singapore, Singapore 117456, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore.
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26
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Kiełbowski K, Bakinowska E, Gorący-Rosik A, Figiel K, Judek R, Rosik J, Dec P, Modrzejewski A, Pawlik A. DNA and RNA Methylation in Rheumatoid Arthritis-A Narrative Review. EPIGENOMES 2025; 9:2. [PMID: 39846569 PMCID: PMC11755448 DOI: 10.3390/epigenomes9010002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 12/28/2024] [Accepted: 01/06/2025] [Indexed: 01/24/2025] Open
Abstract
Rheumatoid arthritis (RA) is a progressive autoimmune disease leading to structural and functional joint damage and, eventually, to physical disability. The pathogenesis of the disease is highly complex and involves interactions between fibroblast-like synoviocytes (FLSs) and immune cells, which stimulate the secretion of pro-inflammatory factors, leading to chronic inflammation. In recent years, studies have demonstrated the importance of epigenetics in RA. Specifically, epigenetic alterations have been suggested to serve as diagnostic and treatment biomarkers, while epigenetic mechanisms are thought to be involved in the pathogenesis of RA. Epigenetic regulators coordinate gene expression, and in the case of inflammatory diseases, they regulate the expression of a broad range of inflammatory molecules. In this review, we discuss current evidence on the involvement of DNA and RNA methylation in RA.
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Affiliation(s)
- Kajetan Kiełbowski
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (K.K.); (E.B.); (K.F.); (R.J.); (J.R.)
| | - Estera Bakinowska
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (K.K.); (E.B.); (K.F.); (R.J.); (J.R.)
| | - Anna Gorący-Rosik
- Department of Clinical and Molecular Biochemistry, Pomeranian Medical University, 70-111 Szczecin, Poland;
| | - Karolina Figiel
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (K.K.); (E.B.); (K.F.); (R.J.); (J.R.)
| | - Roksana Judek
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (K.K.); (E.B.); (K.F.); (R.J.); (J.R.)
| | - Jakub Rosik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (K.K.); (E.B.); (K.F.); (R.J.); (J.R.)
| | - Paweł Dec
- Department of Plastic and Reconstructive Surgery, 109 Military Hospital, 71-422 Szczecin, Poland
| | - Andrzej Modrzejewski
- Clinical Department of General Surgery, Pomeranian Medical University in Szczecin, Piotra Skargi 9-11, 70-965 Szczecin, Poland;
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (K.K.); (E.B.); (K.F.); (R.J.); (J.R.)
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27
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Chuleerarux N, Makkoukdji N, Satnarine T, Kuhn JE, Nopsopon T, Valyasevi P, Schmidt FB, Kleiner G, Gans M. Inborn Errors of Immunity Presenting with Early-Onset Severe Atopy. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:62. [PMID: 39859044 PMCID: PMC11767231 DOI: 10.3390/medicina61010062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 12/30/2024] [Accepted: 12/31/2024] [Indexed: 01/27/2025]
Abstract
Inborn errors of immunity (IEIs), also known as primary immunodeficiencies, are a group of genetic disorders affecting the development and function of the immune system. While IEIs traditionally present with recurrent infections, an increasing number of cases manifest with early-onset severe atopy, including atopic dermatitis, food allergies, asthma, and allergic rhinitis-features that are often overlooked. This can lead to delayed diagnosis and treatment, which is crucial for IEI patients due to the risk of severe infections. We conducted a literature search and reviewed all IEIs that can present with early-onset severe atopy. The hallmark features of these disorders often include early-onset, persistent, and severe atopic dermatitis, food allergies, and recurrent episodes of asthma, which may be refractory to treatments. Additionally, we discuss the importance of recognizing such severe atopy as a potential indicator of an underlying immune deficiency, particularly when accompanied by unusual infections, growth failure, or autoimmunity. This review aims to raise awareness of this association and emphasize the need for early diagnosis and genetic testing in patients with atypical or treatment-resistant allergic diseases, allowing for more timely diagnosis of underlying immunodeficiencies and appropriate treatments.
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Affiliation(s)
- Nipat Chuleerarux
- Department of Internal Medicine, Jackson Memorial Hospital, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Nadia Makkoukdji
- Department of Pediatrics, Jackson Memorial Holtz Children’s Hospital, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Travis Satnarine
- Department of Pediatrics, Jackson Memorial Holtz Children’s Hospital, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Jessica Elise Kuhn
- Department of Pediatrics, Jackson Memorial Holtz Children’s Hospital, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Tanawin Nopsopon
- Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Peerada Valyasevi
- Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Fernanda Bellodi Schmidt
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Gary Kleiner
- Division of Allergy/Immunology, Department of Pediatrics, Jackson Memorial Holtz Children’s Hospital, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Melissa Gans
- Division of Allergy/Immunology, Department of Pediatrics, Jackson Memorial Holtz Children’s Hospital, University of Miami Miller School of Medicine, Miami, FL 33136, USA
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28
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Nawrocki M, Huber S. Using Specific Reporter Mice to Assess CD4 + T Cell Transdifferentiation. Methods Mol Biol 2025; 2904:125-132. [PMID: 40220230 DOI: 10.1007/978-1-0716-4414-0_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/14/2025]
Abstract
The hallmark of the adaptive immune response is its ability to adjust to the offending agents via antigen specificity and the type of immune mechanisms involved in the host defense. The cytokine milieu present in the inflammatory environment and the strength of T cell receptor (TCR) signaling control the differentiation of CD4+ T cells into specific effector or regulatory lineages. Nevertheless, CD4+ T cell differentiation is a dynamic ongoing process allowing for the plasticity of lineages, with CD4+ T cells possessing phenotypes of more than one effector lineage and transdifferentiation between effector states or from an effector into a regulatory phenotype. In this protocol, we describe how the use of reporter mice can be employed for studying cell transdifferentiation of CD4+ T cells in vitro.
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Affiliation(s)
- Mikolaj Nawrocki
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Samuel Huber
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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29
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Golzari-Sorkheh M, Yoganathan K, Chen ELY, Singh J, Zúñiga-Pflücker JC. T Cell Development: From T-Lineage Specification to Intrathymic Maturation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1471:81-137. [PMID: 40067585 DOI: 10.1007/978-3-031-77921-3_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/13/2025]
Abstract
T cell development occurs in the thymus in both mice and humans. Upon entry into the thymus, bone marrow-derived blood-borne progenitors receive instructive signals, including Notch signaling, to eliminate their potential to develop into alternative immune lineages while committing to the T cell fate. Upon T-lineage commitment, developing T cells receive further instructional cues to generate different T cell sublineages, which together possess diverse immunological functions to provide host immunity. Over the years, numerous studies have contributed to a greater understanding of key thymic signals that govern T cell differentiation and subset generation. Here, we review these critical signaling factors that govern the different stages of both mouse and human T cell development, while also focusing on the transcriptional changes that mediate T cell identity and diversity.
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Affiliation(s)
- Mahdieh Golzari-Sorkheh
- Department of Immunology, University of Toronto & Sunnybrook Research Institute, Toronto, ON, Canada
| | - Kogulan Yoganathan
- Department of Immunology, University of Toronto & Sunnybrook Research Institute, Toronto, ON, Canada
| | - Edward L Y Chen
- Department of Immunology, University of Toronto & Sunnybrook Research Institute, Toronto, ON, Canada
| | - Jastaranpreet Singh
- Department of Immunology, University of Toronto & Sunnybrook Research Institute, Toronto, ON, Canada
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30
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Schnell JT, Briviesca RL, Kim T, Charbonnier LM, Henderson LA, van Wijk F, Nigrovic PA. The 'T reg paradox' in inflammatory arthritis. Nat Rev Rheumatol 2025; 21:9-21. [PMID: 39653758 DOI: 10.1038/s41584-024-01190-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/06/2024] [Indexed: 12/12/2024]
Abstract
Classic regulatory T (Treg) cells expressing CD4 and the hallmark transcription factor FOXP3 are integral to the prevention of multi-system autoimmunity. However, immune-mediated arthritis is often associated with increased numbers of Treg cells in the inflamed joints. To understand these seemingly conflicting observations, which we collectively describe as 'the Treg paradox', we provide an overview of Treg cell biology with a focus on Treg cell heterogeneity, function and dysfunction in arthritis. We discuss how the inflamed environment constrains the immunosuppressive activity of Treg cells while also promoting the differentiation of TH17-like Treg cell, exTreg cell (effector T cells that were formerly Treg cells), and osteoclastogenic Treg cell subsets that mediate tissue injury. We present a new framework to understand Treg cells in joint inflammation and define potential strategies for Treg cell-directed interventions in human inflammatory arthritis.
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Affiliation(s)
- Julia T Schnell
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA, USA
- Department of Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
| | | | - Taehyeung Kim
- Division of Immunology, Boston Children's Hospital, Boston, MA, USA
| | | | | | - Femke van Wijk
- Centre for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Peter A Nigrovic
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA, USA.
- Division of Immunology, Boston Children's Hospital, Boston, MA, USA.
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31
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Weinstein KN, Domeier PP, Ziegler SF. A splice of life: the discovery, function, and clinical implications of FOXP3 isoforms in autoimmune disease. Int Immunol 2024; 37:83-90. [PMID: 39136284 DOI: 10.1093/intimm/dxae049] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 08/12/2024] [Indexed: 12/28/2024] Open
Abstract
Regulatory T cells (Tregs) are a specialized subset of CD4+ T cells essential for the maintenance of immune homeostasis and prevention of autoimmunity. Treg lineage and functions are programmed by the X-chromosome encoded transcription factor forkhead box P3 (FOXP3). In humans, multiple FOXP3 isoforms are generated through alternative splicing. A full-length isoform containing all coding exons (FOXP3-FL) and a version lacking the second exon (FOXP3-ΔE2) are the predominant FOXP3 isoforms. Additionally, there are two minor isoforms lacking either exon 7 (FOXP3-ΔE7) and both exons 2 and 7 (FOXP3-ΔE2ΔE7). Although healthy humans express approximately equal levels of the FOXP3-FL and FOXP3-ΔE2 isoforms, sole expression of FOXP3-ΔE2 results in the development of a systemic autoimmune disease that resembles immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. These clinical observations strongly suggest functional defects in suppression by Tregs programmed by the FOXP3-ΔE2 isoform. Work from the past two decades has provided phenotypic and functional evidence of differences between Tregs programmed by the FOXP3-FL, FOXP3-ΔE2, and FOXP3-ΔE7 isoforms. In this review, we discuss the discovery of the FOXP3 isoforms, differences in the phenotype and function of Tregs programmed by different FOXP3 isoforms, and the role that these isoforms are known to play in autoimmunity.
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Affiliation(s)
- Kristin N Weinstein
- Center for Fundamental Immunology, Benaroya Research Institute, Seattle, WA, 98101, USA
- Department of Immunology, University of Washington, Seattle, WA, USA
| | - Phillip P Domeier
- Center for Fundamental Immunology, Benaroya Research Institute, Seattle, WA, 98101, USA
| | - Steven F Ziegler
- Center for Fundamental Immunology, Benaroya Research Institute, Seattle, WA, 98101, USA
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Ye L, Song X, Cui Y, Wu S, Wang Y, Zhang T, Weng W, Ge T. Sirolimus alleviated intractable diarrhea of IPEX syndrome: a case report and literature review. BMC Pediatr 2024; 24:806. [PMID: 39696094 PMCID: PMC11653752 DOI: 10.1186/s12887-024-05264-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Accepted: 11/19/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare single-gene X-linked immunodeficiency disease caused by mutations in the forkhead box protein 3 (FOXP3) gene. The typical clinical manifestations of IPEX mainly include severe atopic dermatitis, insulin-dependent type 1 diabetes mellitus, and intractable diarrhea. CASE PRESENTATION Here, we report a boy with intractable diarrhea diagnosed with early-onset IPEX syndrome due to the c.434C > T (p.Ala145Val) mutation in exon 4 of the FOXP3 gene. The patient experienced intractable diarrhea and severe weight loss, and his clinical symptoms could not be alleviated by conventional supportive and anti-infection treatment. Sirolimus, an immunosuppressant, preferentially inhibits effector T cells while allowing the proliferation of Tregs and is used to treat IPEX patients and alleviate intractable diarrhea. CONCLUSION We reviewed the literature on the use of sirolimus for the treatment of IPEX syndrome over the past two decades.
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Affiliation(s)
- Lin Ye
- Department of Gastroenterology, Hepatology, and Nutrition, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, 355 Luding Road, Shanghai, 200062, China
| | - Xue Song
- Department of Gastroenterology, Hepatology, and Nutrition, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, 355 Luding Road, Shanghai, 200062, China
| | - Yun Cui
- Department of Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200062, China
| | - Shengnan Wu
- Department of Clinical Laboratory, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, 355 Luding Road, Shanghai, 200062, China
| | - Yizhong Wang
- Department of Gastroenterology, Hepatology, and Nutrition, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, 355 Luding Road, Shanghai, 200062, China
| | - Ting Zhang
- Department of Gastroenterology, Hepatology, and Nutrition, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, 355 Luding Road, Shanghai, 200062, China
| | - Wenhao Weng
- Department of Clinical Laboratory, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, 355 Luding Road, Shanghai, 200062, China.
| | - Ting Ge
- Department of Gastroenterology, Hepatology, and Nutrition, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, 355 Luding Road, Shanghai, 200062, China.
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Bulliard Y, Freeborn R, Uyeda MJ, Humes D, Bjordahl R, de Vries D, Roncarolo MG. From promise to practice: CAR T and Treg cell therapies in autoimmunity and other immune-mediated diseases. Front Immunol 2024; 15:1509956. [PMID: 39697333 PMCID: PMC11653210 DOI: 10.3389/fimmu.2024.1509956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 11/12/2024] [Indexed: 12/20/2024] Open
Abstract
Autoimmune diseases, characterized by the immune system's attack on the body's own tissues, affect millions of people worldwide. Current treatments, which primarily rely on broad immunosuppression and symptom management, are often associated with significant adverse effects and necessitate lifelong therapy. This review explores the next generation of therapies for immune-mediated diseases, including chimeric antigen receptor (CAR) T cell and regulatory T cell (Treg)-based approaches, which offer the prospect of targeted, durable disease remission. Notably, we highlight the emergence of CD19-targeted CAR T cell therapies, and their ability to drive sustained remission in B cell-mediated autoimmune diseases, suggesting a possible paradigm shift. Further, we discuss the therapeutic potential of Type 1 and FOXP3+ Treg and CAR-Treg cells, which aim to achieve localized immune modulation by targeting their activity to specific tissues or cell types, thereby minimizing the risk of generalized immunosuppression. By examining the latest advances in this rapidly evolving field, we underscore the potential of these innovative cell therapies to address the unmet need for long-term remission and potential tolerance induction in individuals with autoimmune and immune-mediated diseases.
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Affiliation(s)
- Yannick Bulliard
- Department of Research and Development, Tr1X, Inc., San Diego, CA, United States
| | - Robert Freeborn
- Department of Research and Development, Tr1X, Inc., San Diego, CA, United States
| | - Molly Javier Uyeda
- Department of Research and Development, Tr1X, Inc., San Diego, CA, United States
| | - Daryl Humes
- Department of Research and Development, Tr1X, Inc., San Diego, CA, United States
| | - Ryan Bjordahl
- Department of Research and Development, Tr1X, Inc., San Diego, CA, United States
| | - David de Vries
- Department of Research and Development, Tr1X, Inc., San Diego, CA, United States
| | - Maria Grazia Roncarolo
- Department of Research and Development, Tr1X, Inc., San Diego, CA, United States
- Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States
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Macon CE, Yang A, Patel D, North JP, Rosenblum MD, Cohen JN. CD4 + T Cells Occupy Perivascular and Perifollicular Niches in Healthy Human Skin. Exp Dermatol 2024; 33:e70023. [PMID: 39673225 DOI: 10.1111/exd.70023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 11/27/2024] [Accepted: 11/28/2024] [Indexed: 12/16/2024]
Abstract
Regulatory T cells (Tregs) are specialised T lymphocytes that sit at the nexus of immune regulation and tissue repair. While it is appreciated that a substantial number of Tregs are present in healthy human skin, less is known about their microanatomic spatial localisation. Knowledge about the specialised niches that Tregs occupy may aid in rational drug development to treat dermatologic diseases. Thus, we performed multiplexed immunohistochemistry for CD4 and FOXP3 (the lineage-defining transcription factor of Tregs) on healthy skin sections obtained from eight different cutaneous sites, and quantified Tregs and Tcon in distinct regions. We found that Tregs (CD4+ FOXP3+) comprised roughly 20% of CD4+ T cells in skin and that Tregs and T-conventional cells (Tcon; CD4+ Foxp3-) are enriched in follicularly dense skin and show preferential accumulation in perivascular and perifollicular niches in the upper dermis. Additionally, male skin shows a significant increase in the numbers of Tregs and Tcon, while female skin shows a higher Tcon:Treg ratio. We also find that the frequency of skin Tregs declines over time. Overall, we conclude that the upper dermal perivascular region is a niche that supports the accumulation of CD4+ T cells in steady-state human skin.
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Affiliation(s)
- Courtney E Macon
- Department of Dermatology, University of California at San Francisco, San Francisco, California, USA
| | - Annie Yang
- Department of Dermatology, University of California at San Francisco, San Francisco, California, USA
| | - Dhara Patel
- Department of Dermatology, University of California at San Francisco, San Francisco, California, USA
| | - Jeffrey P North
- Department of Dermatology, University of California at San Francisco, San Francisco, California, USA
- Department of Pathology, University of California at San Francisco, San Francisco, California, USA
| | - Michael D Rosenblum
- Department of Dermatology, University of California at San Francisco, San Francisco, California, USA
| | - Jarish N Cohen
- Department of Dermatology, University of California at San Francisco, San Francisco, California, USA
- Department of Pathology, University of California at San Francisco, San Francisco, California, USA
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35
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Shang S, Zhao C, Lin J. Therapeutic potentials of adoptive cell therapy in immune-mediated neuropathy. J Autoimmun 2024; 149:103305. [PMID: 39265193 DOI: 10.1016/j.jaut.2024.103305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 07/06/2024] [Accepted: 08/23/2024] [Indexed: 09/14/2024]
Abstract
Immune-mediated neuropathy (IMN) is a group of heterogenous neuropathies caused by intricate autoimmune responses. For now, known mechanisms of different IMN subtypes involve the production of autoantibodies, complement activation, enhanced inflammation and subsequent axonal/demyelinating nerve damages. Recent therapeutic studies mainly focus on specific antibodies and small molecule inhibitors previously approved in rheumatoid diseases. Initial strategies based on the pathophysiologic features of IMN should be explored. Adoptive cell therapy (ACT) refers to the emerging immunotherapies in which circulating immunocytes are collected from peripheral blood and modified with killing and immunomodulatory capacities. It consists of chimeric antigen receptor-T cell therapy, T cell receptor-engineered T cell, CAR-Natural killer cell therapy, and others. In the last decade, ACT has demonstrated extraordinary potentials in treating cancers, infectious diseases and autoimmune diseases. Versatile combinations of targets, chimeric domains and effector cells greatly empower ACT to treat complicated immune disorders. In this review, we summarized the advances of ACT and envisioned suitable strategies for different IMN subtypes.
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MESH Headings
- Humans
- Immunotherapy, Adoptive/methods
- Animals
- Receptors, Chimeric Antigen/immunology
- Receptors, Chimeric Antigen/metabolism
- Receptors, Chimeric Antigen/genetics
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
- Killer Cells, Natural/immunology
- Killer Cells, Natural/metabolism
- Killer Cells, Natural/transplantation
- Receptors, Antigen, T-Cell/metabolism
- Receptors, Antigen, T-Cell/immunology
- Receptors, Antigen, T-Cell/genetics
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Affiliation(s)
- Siqi Shang
- Department of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; Rare Disease Center, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; National Center for Neurological Disorders (NCND), Shanghai, China
| | - Chongbo Zhao
- Department of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; Rare Disease Center, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; National Center for Neurological Disorders (NCND), Shanghai, China
| | - Jie Lin
- Department of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; Rare Disease Center, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; National Center for Neurological Disorders (NCND), Shanghai, China.
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Ohara D, Takeuchi Y, Hirota K. Type 17 immunity: novel insights into intestinal homeostasis and autoimmune pathogenesis driven by gut-primed T cells. Cell Mol Immunol 2024; 21:1183-1200. [PMID: 39379604 PMCID: PMC11528014 DOI: 10.1038/s41423-024-01218-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 09/11/2024] [Indexed: 10/10/2024] Open
Abstract
The IL-23 signaling pathway in both innate and adaptive immune cells is vital for orchestrating type 17 immunity, which is marked by the secretion of signature cytokines such as IL-17, IL-22, and GM-CSF. These proinflammatory mediators play indispensable roles in maintaining intestinal immune equilibrium and mucosal host defense; however, their involvement has also been implicated in the pathogenesis of chronic inflammatory disorders, such as inflammatory bowel diseases and autoimmunity. However, the implications of type 17 immunity across diverse inflammation models are complex. This review provides a comprehensive overview of the multifaceted roles of these cytokines in maintaining gut homeostasis and in perturbing gut barrier integrity, leading to acute and chronic inflammation in various models of gut infection and colitis. Additionally, this review focuses on type 17 immunity interconnecting multiple organs in autoimmune conditions, with a particular emphasis on the pathogenesis of autoimmune arthritis and neuroinflammation driven by T cells primed within the gut microenvironment.
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Affiliation(s)
- Daiya Ohara
- Laboratory of Integrative Biological Science, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Yusuke Takeuchi
- Laboratory of Integrative Biological Science, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Keiji Hirota
- Laboratory of Integrative Biological Science, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.
- ImmunoSensation Cluster of Excellence, University of Bonn, Bonn, Germany.
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37
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Wang Y, Xue L. Decoding the role of FOXP3 in esophageal cancer: Underlying mechanisms and therapeutic implications. Biochim Biophys Acta Rev Cancer 2024; 1879:189211. [PMID: 39532205 DOI: 10.1016/j.bbcan.2024.189211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 10/05/2024] [Accepted: 10/31/2024] [Indexed: 11/16/2024]
Abstract
Esophageal cancer is a significant contributor to cancer-related mortality, and its poor prognosis is primarily attributed to the aggressive nature of the tumor and challenges in early detection. Currently, there are no ideal drugs developed for treatment, making it crucial to explore potential biomarkers and molecular targets for esophageal cancer. FOXP3, as a transcription factor and major regulator of regulatory T cells, not only plays a role in promoting or inhibiting tumor development in various types of cancer cells including esophageal cancer cells but also influences the function of Treg cells by regulating the expression of multiple genes. This paper provides an in-depth discussion on the functional properties, regulatory mechanisms, key signaling pathways, as well as the role and potential application of FOXP3 in treating esophageal cancer. Furthermore, it comprehensively analyzes the complex role of this transcription factor within the tumor immune microenvironment with an aim to aid in developing new potential targets for esophageal cancer treatment.
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Affiliation(s)
- Yuanyuan Wang
- Department of Thoracic Surgery, Shanghai Changzheng Hospital, Second Affiliated Hospital of Naval Military Medical University, 200003 Shanghai, China.
| | - Lei Xue
- Department of Thoracic Surgery, Shanghai Changzheng Hospital, Second Affiliated Hospital of Naval Military Medical University, 200003 Shanghai, China.
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38
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Huang Q, Zhu J. Regulatory T cell-based therapy in type 1 diabetes: Latest breakthroughs and evidence. Int Immunopharmacol 2024; 140:112724. [PMID: 39098233 DOI: 10.1016/j.intimp.2024.112724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 07/10/2024] [Accepted: 07/16/2024] [Indexed: 08/06/2024]
Abstract
Autoimmune diseases (ADs) are among the most significant health complications, with their incidence rising in recent years. Type 1 diabetes (T1D), an AD, targets the insulin-producing β cells in the pancreas, leading to chronic insulin deficiency in genetically susceptible individuals. Regulatory immune cells, particularly T-cells (Tregs), have been shown to play a crucial role in the pathogenesis of diabetes by modulating immune responses. In diabetic patients, Tregs often exhibit diminished effectiveness due to various factors, such as instability in forkhead box P3 (Foxp3) expression or abnormal production of the proinflammatory cytokine interferon-gamma (IFN-γ) by autoreactive T-cells. Consequently, Tregs represent a potential therapeutic target for diabetes treatment. Building on the successful clinical outcomes of chimeric antigen receptor (CAR) T-cell therapy in cancer treatment, particularly in leukemias, the concept of designing and utilizing CAR Tregs for ADs has emerged. This review summarizes the findings on Treg targeting in T1D and discusses the benefits and limitations of this treatment approach for patients suffering from T1D.
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Affiliation(s)
- Qiongxiao Huang
- Center for Reproductive Medicine, Department of Reproductive Endocrinology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang 310014, China
| | - Jing Zhu
- Center for Reproductive Medicine, Department of Reproductive Endocrinology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang 310014, China.
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39
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Fogarasi M, Dima S. Immunomodulatory Functions of TNF-Related Apoptosis-Inducing Ligand in Type 1 Diabetes. Cells 2024; 13:1676. [PMID: 39451194 PMCID: PMC11506310 DOI: 10.3390/cells13201676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 10/01/2024] [Accepted: 10/09/2024] [Indexed: 10/26/2024] Open
Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF protein superfamily and was initially identified as a protein capable of inducing apoptosis in cancer cells. In addition, TRAIL can promote pro-survival and proliferation signaling in various cell types. Subsequent studies have demonstrated that TRAIL plays several important roles in immunoregulation, immunosuppression, and immune effector functions. Type 1 diabetes (T1D) is an autoimmune disease characterized by hyperglycemia due to the loss of insulin-producing β-cells, primarily driven by T-cell-mediated pancreatic islet inflammation. Various genetic, epigenetic, and environmental factors, in conjunction with the immune system, contribute to the initiation, development, and progression of T1D. Recent reports have highlighted TRAIL as an important immunomodulatory molecule with protective effects on pancreatic islets. Experimental data suggest that TRAIL protects against T1D by reducing the proliferation of diabetogenic T cells and pancreatic islet inflammation and restoring normoglycemia in animal models. In this review, we aimed to summarize the consequences of TRAIL action in T1D, focusing on and discussing its signaling mechanisms, role in the immune system, and protective effects in T1D.
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Affiliation(s)
- Marton Fogarasi
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Simona Dima
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, 022328 Bucharest, Romania
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
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40
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Yazdanpanah N, Rezaei N. The multidisciplinary approach to diagnosing inborn errors of immunity: a comprehensive review of discipline-based manifestations. Expert Rev Clin Immunol 2024; 20:1237-1259. [PMID: 38907993 DOI: 10.1080/1744666x.2024.2372335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 06/21/2024] [Indexed: 06/24/2024]
Abstract
INTRODUCTION Congenital immunodeficiency is named primary immunodeficiency (PID), and more recently inborn errors of immunity (IEI). There are more than 485 conditions classified as IEI, with a wide spectrum of clinical and laboratory manifestations. AREAS COVERED Regardless of the developing knowledge of IEI, many physicians do not think of IEI when approaching the patient's complaint, which leads to delayed diagnosis, misdiagnosis, serious infectious and noninfectious complications, permanent end-organ damage, and even death. Due to the various manifestations of IEI and the wide spectrum of associated conditions, patients refer to specialists in different disciplines of medicine and undergo - mainly symptomatic - treatments, and because IEI are not included in physicians' differential diagnosis, the main disease remains undiagnosed. EXPERT OPINION A multidisciplinary approach may be a proper solution. Manifestations and the importance of a multidisciplinary approach in the diagnosis of main groups of IEI are discussed in this article.
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Affiliation(s)
- Niloufar Yazdanpanah
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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41
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de Kivit S, Mensink M, Kostidis S, Derks RJE, Zaal EA, Heijink M, Verleng LJ, de Vries E, Schrama E, Blomberg N, Berkers CR, Giera M, Borst J. Immune suppression by human thymus-derived effector Tregs relies on glucose/lactate-fueled fatty acid synthesis. Cell Rep 2024; 43:114681. [PMID: 39180751 DOI: 10.1016/j.celrep.2024.114681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 07/10/2024] [Accepted: 08/08/2024] [Indexed: 08/26/2024] Open
Abstract
Regulatory T cells (Tregs) suppress pro-inflammatory conventional T cell (Tconv) responses. As lipids impact cell signaling and function, we compare the lipid composition of CD4+ thymus-derived (t)Tregs and Tconvs. Lipidomics reveal constitutive enrichment of neutral lipids in Tconvs and phospholipids in tTregs. TNFR2-co-stimulated effector tTregs and Tconvs are both glycolytic, but only in tTregs are glycolysis and the tricarboxylic acid (TCA) cycle linked to a boost in fatty acid (FA) synthesis (FAS), supported by relevant gene expression. FA chains in tTregs are longer and more unsaturated than in Tconvs. In contrast to Tconvs, tTregs effectively use either lactate or glucose for FAS and rely on this process for proliferation. FASN and SCD1, enzymes responsible for FAS and FA desaturation, prove essential for the ability of tTregs to suppress Tconvs. These data illuminate how effector tTregs can thrive in inflamed or cancerous tissues with limiting glucose but abundant lactate levels.
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Affiliation(s)
- Sander de Kivit
- Department of Immunology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands; Oncode Institute, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
| | - Mark Mensink
- Department of Immunology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands; Oncode Institute, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
| | - Sarantos Kostidis
- Center for Proteomics and Metabolomics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
| | - Rico J E Derks
- Center for Proteomics and Metabolomics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
| | - Esther A Zaal
- Division of Cell Biology, Metabolism, and Cancer, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, the Netherlands
| | - Marieke Heijink
- Center for Proteomics and Metabolomics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
| | - Lotte J Verleng
- Department of Immunology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands; Oncode Institute, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
| | - Evert de Vries
- Department of Immunology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands; Oncode Institute, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
| | - Ellen Schrama
- Department of Immunology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands; Oncode Institute, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
| | - Niek Blomberg
- Center for Proteomics and Metabolomics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
| | - Celia R Berkers
- Division of Cell Biology, Metabolism, and Cancer, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, the Netherlands
| | - Martin Giera
- Center for Proteomics and Metabolomics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
| | - Jannie Borst
- Department of Immunology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands; Oncode Institute, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
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42
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Peeters JGC, Silveria S, Ozdemir M, Ramachandran S, DuPage M. Hyperactivating EZH2 to augment H3K27me3 levels in regulatory T cells enhances immune suppression by driving early effector differentiation. Cell Rep 2024; 43:114724. [PMID: 39264807 PMCID: PMC12052300 DOI: 10.1016/j.celrep.2024.114724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 07/17/2024] [Accepted: 08/21/2024] [Indexed: 09/14/2024] Open
Abstract
The immunosuppressive function of regulatory T (Treg) cells is essential for maintaining immune homeostasis. Enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 (H3K27) methyltransferase, plays a key role in maintaining Treg cell function upon CD28 co-stimulation, and Ezh2 deletion in Treg cells causes autoimmunity. Here, we assess whether increasing H3K27me3 levels, by using an Ezh2Y641F gain-of-function mutation, will improve Treg cell function. We find that Treg cells expressing Ezh2Y641F display an effector Treg phenotype, are poised for improved homing to organ tissues, and can accelerate remission from autoimmunity. The H3K27me3 landscape and transcriptome of naive Ezh2Y641F Treg cells exhibit a redistribution of H3K27me3 modifications that recapitulates the gene expression profile of activated Ezh2WT Treg cells after CD28 co-stimulation. Altogether, increased H3K27me3 levels promote the differentiation of effector Treg cells that can better suppress autoimmunity.
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Affiliation(s)
- Janneke G C Peeters
- Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Stephanie Silveria
- Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Merve Ozdemir
- Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Srinivas Ramachandran
- Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045, USA; RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, CO 80045, USA.
| | - Michel DuPage
- Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
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Shi Y, Zhang W, Jia Q, Zhong X, Iyer P, Wu H, Yuan YC, Zhao Y, Zhang L, Wang L, Jia Z, Kuo YH, Sun Z. Cancer-associated SF3B1-K700E mutation controls immune responses by regulating T reg function via aberrant Anapc13 splicing. SCIENCE ADVANCES 2024; 10:eado4274. [PMID: 39303038 PMCID: PMC11414738 DOI: 10.1126/sciadv.ado4274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 08/14/2024] [Indexed: 09/22/2024]
Abstract
Recurrent somatic mutations in spliceosome factor 3b subunit 1 (SF3B1) are identified in hematopoietic malignancies, with SF3B1-K700E being the most common one. Here, we show that regulatory T cell (Treg)-specific expression of SF3B1-K700E (Sf3b1K700Efl/+/Foxp3YFP-Cre) results in spontaneous autoimmune phenotypes. CD4+ T cells from Sf3b1K700Efl/+/Foxp3YFP-Cre mice display defective Treg differentiation and inhibitory function, which is demonstrated by failed prevention of adoptive transfer colitis by Sf3b1K700Efl/+/Foxp3YFP-Cre Tregs. Mechanically, SF3B1-K700E induces an aberrant splicing event that results in reduced expression of a cell proliferation regulator Anapc13 due to the insertion of a 231-base pair DNA fragment to the 5' untranslated region. Forced expression of the Anapc13 gene restores the differentiation and ability of Sf3b1K700Efl/+/Foxp3YFP-Cre Tregs to prevent adoptive transfer colitis. In addition, acute myeloid leukemia grows faster in aged, but not young, Sf3b1K700Efl/+/Foxp3YFP-Cre mice compared to Foxp3YFP-Cre mice. Our results highlight the impact of cancer-associated SF3B1 mutation on immune responses, which affect cancer development.
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Affiliation(s)
- Yun Shi
- Department of Immunology & Theranostics, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA
| | - Wencan Zhang
- Department of Immunology & Theranostics, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA
| | - Qiong Jia
- Department of Botany & Plant Sciences, University of California, Riverside, CA 92527, USA
| | - Xiancai Zhong
- Department of Immunology & Theranostics, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA
| | - Prajish Iyer
- Department of System Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA
| | - Hongmin Wu
- Department of Immunology & Theranostics, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA
| | - Yate-Ching Yuan
- Translational Bioinformatics, Department of Computational Quantitative Medicine, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA
| | - Yuqi Zhao
- Integrated Genomics Core, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA
| | - Lianjun Zhang
- Gehr Family Center for Leukemia Research, Department of Hematological Malignancies Translational Science, Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA
| | - Lili Wang
- Department of System Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA
| | - Zhenyu Jia
- Department of Botany & Plant Sciences, University of California, Riverside, CA 92527, USA
| | - Ya-Huei Kuo
- Gehr Family Center for Leukemia Research, Department of Hematological Malignancies Translational Science, Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA
| | - Zuoming Sun
- Department of Immunology & Theranostics, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA
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Bekis Bozkurt H, Bayram Catak F, Sahin A, Yalcin Gungoren E, Gemici Karaarslan B, Yakici N, Yorgun Altunbas M, Catak MC, Can S, Amirov R, Bozkurt S, Ozturk N, Bilgic Eltan S, Kasap N, Bal Cetinkaya F, Orhan F, Arga M, Cavkaytar O, Kiykim A, Karakoc-Aydiner E, Ozen A, Baris S. Diverse Clinical and Immunological Profiles in Patients with IPEX Syndrome: a Multicenter Analysis from Turkey. J Clin Immunol 2024; 45:9. [PMID: 39283523 DOI: 10.1007/s10875-024-01791-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 08/19/2024] [Indexed: 12/06/2024]
Abstract
PURPOSE Immunodysregulation, Polyendocrinopathy, Enteropathy, and X-linked syndrome (IPEX), caused by pathogenic FOXP3 variants, is a rare autoimmune disorder with diverse clinical features, including early-onset diabetes, eczema, and enteropathy. Atypical cases show milder symptoms and unique signs, requiring different treatments. Therefore, there are ambiguities in the accurate diagnosis and management of IPEX. We sought to present clinical, genetic, and immunological assessments of 12 IPEX patients with long-term follow-up to facilitate the diagnosis and management of the disease. METHODS Clinical findings and treatment options of the patients were collected over time. Lymphocyte subpopulations, protein expressions, regulatory T (Treg) and circulating T follicular helper (cTFH) cells, and T-cell proliferation were analyzed. RESULTS Predominant presentations included autoimmunity (91.6%), failure to thrive (66.7%), and eczema (58.3%). There were four classical and eight atypical IPEX individuals. Allergic manifestations were more common in atypical patients. Notably, chronic diarrhea demonstrated heightened severity compared to other manifestations. Four patients (33.3%) demonstrated eosinophilia, and nine (75%) showed high serum IgE levels. Most patients exhibited normal percentages of Treg cells with reduced CD25, FOXP3, and CTLA-4 expressions, corrected after hematopoietic stem cell transplantation (HSCT). Compared to healthy controls, the TH2-like skewing accompanied by reduced TH17-like responses was observed in cTFH and Treg cells of patients. Overall, nine patients (75%) received immunosuppressants (ISs), and six (50%) underwent HSCT, which was the only treatment revealing sustained control. Sirolimus was used in six patients and showed better control than other ISs. CONCLUSIONS The first cohort from Turkey with long-term follow-up results, comparing typical and atypical cases, provides insights into the outcomes of different therapeutic modalities and T- cell subtype changes in IPEX syndrome.
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MESH Headings
- Humans
- Turkey
- Male
- Child, Preschool
- Forkhead Transcription Factors/genetics
- Forkhead Transcription Factors/metabolism
- Genetic Diseases, X-Linked/diagnosis
- Genetic Diseases, X-Linked/genetics
- Genetic Diseases, X-Linked/immunology
- Genetic Diseases, X-Linked/therapy
- T-Lymphocytes, Regulatory/immunology
- Infant
- Female
- Child
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/diagnosis
- Diabetes Mellitus, Type 1/genetics
- Diabetes Mellitus, Type 1/congenital
- Immune System Diseases/diagnosis
- Immune System Diseases/genetics
- Immune System Diseases/therapy
- Immune System Diseases/congenital
- Autoimmunity
- Adolescent
- Diarrhea
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Affiliation(s)
- Hayrunnisa Bekis Bozkurt
- Faculty of Medicine, Department of Pediatric Allergy and Immunology, Istanbul Medeniyet University, Istanbul, Turkey
| | - Feyza Bayram Catak
- Faculty of Medicine, Department of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Ali Sahin
- Faculty of Medicine, Selcuk University, Konya, Turkey
| | - Ezgi Yalcin Gungoren
- Faculty of Medicine, Department of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Betul Gemici Karaarslan
- Faculty of Medicine, Department of Pediatric Allergy and Immunology, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Nalan Yakici
- Faculty of Medicine, Department of Pediatric Allergy and Immunology, Karadeniz Technical University, Trabzon, Turkey
| | - Melek Yorgun Altunbas
- Faculty of Medicine, Department of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Mehmet Cihangir Catak
- Faculty of Medicine, Department of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Salim Can
- Faculty of Medicine, Department of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Razin Amirov
- Faculty of Medicine, Department of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Selcen Bozkurt
- Faculty of Medicine, Department of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Necmiye Ozturk
- Faculty of Medicine, Department of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Sevgi Bilgic Eltan
- Faculty of Medicine, Department of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Nurhan Kasap
- Faculty of Medicine, Department of Pediatric Allergy and Immunology, Istanbul Medeniyet University, Istanbul, Turkey
| | - Fatma Bal Cetinkaya
- Faculty of Medicine, Department of Pediatric Allergy and Immunology, Istanbul Medeniyet University, Istanbul, Turkey
| | - Fazil Orhan
- Faculty of Medicine, Department of Pediatric Allergy and Immunology, Karadeniz Technical University, Trabzon, Turkey
| | - Mustafa Arga
- Faculty of Medicine, Department of Pediatric Allergy and Immunology, Istanbul Medeniyet University, Istanbul, Turkey
| | - Ozlem Cavkaytar
- Faculty of Medicine, Department of Pediatric Allergy and Immunology, Istanbul Medeniyet University, Istanbul, Turkey
| | - Ayca Kiykim
- Faculty of Medicine, Department of Pediatric Allergy and Immunology, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Elif Karakoc-Aydiner
- Faculty of Medicine, Department of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Ahmet Ozen
- Faculty of Medicine, Department of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Safa Baris
- Faculty of Medicine, Department of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey.
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey.
- The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey.
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Ge J, Yin X, Chen L. Regulatory T cells: masterminds of immune equilibrium and future therapeutic innovations. Front Immunol 2024; 15:1457189. [PMID: 39290699 PMCID: PMC11405253 DOI: 10.3389/fimmu.2024.1457189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Accepted: 08/19/2024] [Indexed: 09/19/2024] Open
Abstract
Regulatory T cells (Tregs), a subset of CD4+T cells marked by the expression of the transcription factor forkhead box protein 3 (Foxp3), are pivotal in maintaining immune equilibrium and preventing autoimmunity. In our review, we addressed the functional distinctions between Foxp3+Tregs and other T cells, highlighting their roles in autoimmune diseases and cancer. We uncovered the dual nature of Tregs: they prevented autoimmune diseases by maintaining self-tolerance while contributing to tumor evasion by suppressing anti-tumor immunity. This study underscored the potential for targeted therapeutic strategies, such as enhancing Treg activity to restore balance in autoimmune diseases or depleting Foxp3+Tregs to augment anti-tumor immune responses in cancer. These insights laid the groundwork for future research and clinical applications, emphasizing the critical role of Foxp3+Tregs in immune regulation and the advancement of next-generation immunotherapies.
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Affiliation(s)
- Junwei Ge
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
- Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Xuan Yin
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
- Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
| | - Lujun Chen
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
- Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
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46
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Liu JQ, Jabbari A, Lin CH, Akkanapally V, Frankel WL, Basu S, He K, Zheng P, Liu Y, Bai XF. IL-27 Gene Therapy Ameliorates IPEX Syndrome Caused by Germline Mutation of Foxp3 Gene: A Major Role for Induction of IL-10. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 213:559-566. [PMID: 38975727 PMCID: PMC11333164 DOI: 10.4049/jimmunol.2400056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 06/13/2024] [Indexed: 07/09/2024]
Abstract
Inactivating mutations of Foxp3, the master regulator of regulatory T cell development and function, lead to immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome in mice and humans. IPEX is a fatal autoimmune disease, with allogeneic stem cell transplant being the only available therapy. In this study, we report that a single dose of adeno-associated virus (AAV)-IL-27 to young mice with naturally occurring Foxp3 mutation (Scurfy mice) substantially ameliorates clinical symptoms, including growth retardation and early fatality. Correspondingly, AAV-IL-27 gene therapy significantly prevented naive T cell activation, as manifested by downregulation of CD62L and upregulation of CD44, and immunopathology typical of IPEX. Because IL-27 is known to induce IL-10, a key effector molecule of regulatory T cells, we evaluated the contribution of IL-10 induction by crossing IL-10-null allele to Scurfy mice. Although IL-10 deficiency does not affect the survival of Scurfy mice, it largely abrogated the therapeutic effect of AAV-IL-27. Our study revealed a major role for IL-10 in AAV-IL-27 gene therapy and demonstrated that IPEX is amenable to gene therapy.
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MESH Headings
- Animals
- Forkhead Transcription Factors/genetics
- Mice
- Interleukin-10/genetics
- Interleukin-10/immunology
- Genetic Therapy/methods
- Germ-Line Mutation
- T-Lymphocytes, Regulatory/immunology
- Genetic Diseases, X-Linked/therapy
- Genetic Diseases, X-Linked/immunology
- Genetic Diseases, X-Linked/genetics
- Interleukins/immunology
- Interleukins/genetics
- Diarrhea/genetics
- Diarrhea/therapy
- Diarrhea/immunology
- Intestinal Diseases/immunology
- Intestinal Diseases/genetics
- Intestinal Diseases/therapy
- Dependovirus/genetics
- Mice, Inbred C57BL
- Immune System Diseases/immunology
- Immune System Diseases/therapy
- Immune System Diseases/genetics
- Immune System Diseases/congenital
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/therapy
- Diabetes Mellitus, Type 1/genetics
- Diabetes Mellitus, Type 1/congenital
- Mice, Knockout
- Lymphocyte Activation/immunology
- Humans
- Interleukin-27/genetics
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Affiliation(s)
- Jin-Qing Liu
- Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Ali Jabbari
- Department of Dermatology, University of Iowa, College of Medicine, Iowa City, Iowa, USA
| | - Cho-Hao Lin
- Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Venu Akkanapally
- Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Wendy L. Frankel
- Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Sujit Basu
- Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Kai He
- Division of Medical Oncology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Pan Zheng
- OncoC4, Inc., 640 Medical Center Drive, Rockville, MD, USA
| | - Yang Liu
- OncoC4, Inc., 640 Medical Center Drive, Rockville, MD, USA
| | - Xue-Feng Bai
- Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
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47
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Miranda-Waldetario MC, Curotto de Lafaille MA. Oral tolerance to dietary antigens and Foxp3 + regulatory T cells. Immunol Rev 2024; 326:8-16. [PMID: 39054615 PMCID: PMC11436310 DOI: 10.1111/imr.13370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/27/2024]
Abstract
Immune tolerance to foods develops in the intestine upon food ingestion and is essential to prevent IgE-mediated food allergy and gut inflammation. In homeostasis, the intestine is a tolerogenic environment that favors the formation of food-specific Foxp3+ regulatory T cells. A tolerogenic intestinal environment depends on colonization by diverse microbiota and exposure to solid foods at a critical period in early life. These early immune responses lead to the induction of antigen-specific Foxp3+ regulatory T cells in draining mesenteric lymph nodes. These peripherally induced regulatory cells circulate and seed the lamina propria of the gut, exerting suppressive function systemically and locally in the intestine. Successful establishment of a tolerogenic intestinal environment in early life sets the stage for oral tolerance to new antigens in adult life.
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Affiliation(s)
- Mariana C.G. Miranda-Waldetario
- Jaffe Food Allergy Institute, Division of Allergy and Immunology, Department of Pediatrics, and Lipschultz Precision Immunology Institute, Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Maria A. Curotto de Lafaille
- Jaffe Food Allergy Institute, Division of Allergy and Immunology, Department of Pediatrics, and Lipschultz Precision Immunology Institute, Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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48
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Kenney HM, Battaglia J, Herman K, Beck LA. Atopic dermatitis and IgE-mediated food allergy: Common biologic targets for therapy and prevention. Ann Allergy Asthma Immunol 2024; 133:262-277. [PMID: 38908432 DOI: 10.1016/j.anai.2024.06.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 06/07/2024] [Accepted: 06/13/2024] [Indexed: 06/24/2024]
Abstract
OBJECTIVE To highlight common mechanistic targets for the treatment of atopic dermatitis (AD) and IgE-mediated food allergy (IgE-FA) with potential to be effective for both diseases and prevent atopic progression. DATA SOURCES Data sources were PubMed searches or National Clinical Trials (NCT)-registered clinical trials related to AD, IgE-FA, and other atopic conditions, especially focused on the pediatric population. STUDY SELECTIONS Human seminal studies and/or articles published in the past decade were emphasized with reference to preclinical models when relevant. NCT-registered clinical trials were filtered by inclusion of pediatric subjects younger than 18 years with special focus on children younger than 12 years as a critical period when AD and IgE-FA diseases may often be concurrent. RESULTS AD and IgE-FA share several pathophysiologic features, including epithelial barrier dysfunction, innate and adaptive immune abnormalities, and microbial dysbiosis, which may be critical for the clinical progression between these diseases. Revolutionary advances in targeted biologic therapies have shown the benefit of inhibiting type 2 immune responses, using dupilumab (anti-interleukin-4Rα) or omalizumab (anti-IgE), to potentially reduce symptom burden for both diseases in pediatric populations. Although the potential for biologics to promote disease remission (AD) or sustained unresponsiveness (IgE-FA) remains unclear, the refinement of biomarkers to predict infants at risk for atopic disorders provides promise for prevention through timely intervention. CONCLUSION AD and IgE-FA exhibit common features that may be leveraged to develop biologic therapeutic strategies to treat both conditions and even prevent atopic progression. Future studies should be designed with consistent age stratification in the pediatric population and standardized regimens of adjuvant oral immunotherapy or dose escalation (IgE-FA) to improve cross-study interpretation.
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Affiliation(s)
- H Mark Kenney
- Department of Medicine, University of Rochester Medical Center, Rochester, New York
| | - Jennifer Battaglia
- Department of Pediatrics, University of Rochester Medical Center, Rochester, New York
| | - Katherine Herman
- Department of Pediatrics, University of Rochester Medical Center, Rochester, New York; Division of Allergy and Immunology, University of Rochester Medical Center, Rochester, New York
| | - Lisa A Beck
- Department of Dermatology, University of Rochester Medical Center, Rochester, New York.
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49
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Havrylov S, Chrystal P, van Baarle S, French CR, MacDonald IM, Avasarala J, Rogers RC, Berry FB, Kume T, Waskiewicz AJ, Lehmann OJ. Pleiotropy in FOXC1-attributable phenotypes involves altered ciliation and cilia-dependent signaling. Sci Rep 2024; 14:20278. [PMID: 39217245 PMCID: PMC11365983 DOI: 10.1038/s41598-024-71159-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 08/26/2024] [Indexed: 09/04/2024] Open
Abstract
Alterations to cilia are responsible for a wide range of severe disease; however, understanding of the transcriptional control of ciliogenesis remains incomplete. In this study we investigated whether altered cilia-mediated signaling contributes to the pleiotropic phenotypes caused by the Forkhead transcription factor FOXC1. Here, we show that patients with FOXC1-attributable Axenfeld-Rieger Syndrome (ARS) have a prevalence of ciliopathy-associated phenotypes comparable to syndromic ciliopathies. We demonstrate that altering the level of Foxc1 protein, via shRNA mediated inhibition, CRISPR/Cas9 mutagenesis and overexpression, modifies cilia length in vitro. These structural changes were associated with substantially perturbed cilia-dependent signaling [Hedgehog (Hh) and PDGFRα], and altered ciliary compartmentalization of the Hh pathway transcription factor, Gli2. Consistent with these data, in primary cultures of murine embryonic meninges, cilia length was significantly reduced in heterozygous and homozygous Foxc1 mutants compared to controls. Meningeal expression of the core Hh signaling components Gli1, Gli3 and Sufu was dysregulated, with comparable dysregulation of Pdgfrα signaling evident from significantly altered Pdgfrα and phosphorylated Pdgfrα expression. On the basis of these clinical and experimental findings, we propose a model that altered cilia-mediated signaling contributes to some FOXC1-induced phenotypes.
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Affiliation(s)
- Serhiy Havrylov
- Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada
- Department of Ophthalmology, 829 Medical Sciences Building, University of Alberta, Edmonton, AB, T6G 2H7, Canada
| | - Paul Chrystal
- Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada
- Department of Ophthalmology, 829 Medical Sciences Building, University of Alberta, Edmonton, AB, T6G 2H7, Canada
| | - Suey van Baarle
- Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada
- Department of Ophthalmology, 829 Medical Sciences Building, University of Alberta, Edmonton, AB, T6G 2H7, Canada
| | - Curtis R French
- Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada
- Department of Ophthalmology, 829 Medical Sciences Building, University of Alberta, Edmonton, AB, T6G 2H7, Canada
- Faculty of Medicine, Memorial University, St. John's, NL, Canada
| | - Ian M MacDonald
- Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada
- Department of Ophthalmology, 829 Medical Sciences Building, University of Alberta, Edmonton, AB, T6G 2H7, Canada
| | - Jagannadha Avasarala
- Department of Neurology, University of Kentucky Medical Center, Lexington, KY, USA
| | | | - Fred B Berry
- Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada
- Department of Surgery, 3002D Li Ka Shing Centre, University of Alberta, Edmonton, AB, Canada
| | - Tsutomu Kume
- Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, USA
| | - Andrew J Waskiewicz
- Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada
| | - Ordan J Lehmann
- Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada.
- Department of Ophthalmology, 829 Medical Sciences Building, University of Alberta, Edmonton, AB, T6G 2H7, Canada.
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50
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Jheng MJ, Kita H. Control of Asthma and Allergy by Regulatory T Cells. Int Arch Allergy Immunol 2024; 186:87-102. [PMID: 39154634 PMCID: PMC11729466 DOI: 10.1159/000540407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 07/15/2024] [Indexed: 08/20/2024] Open
Abstract
BACKGROUND Epithelial barriers, such as the lungs and skin, face the challenge of providing the tissues' physiological function and maintaining tolerance to the commensal microbiome and innocuous environmental factors while defending the host against infectious microbes. Asthma and allergic diseases can result from maladaptive immune responses, resulting in exaggerated and persistent type 2 immunity and tissue inflammation. SUMMARY Among the diverse populations of tissue immune cells, CD4+ regulatory T cells (Treg cells) are central to controlling immune responses and inflammation and restoring tissue homeostasis. Humans and mice that are deficient in Treg cells experience extensive inflammation in their mucosal organs and skin. During past decades, major progress has been made toward understanding the immunobiology of Treg cells and the molecular and cellular mechanisms that control their differentiation and function. It is now clear that Treg cells are not a single cell type and that they demonstrate diversity and plasticity depending on their differentiation stages and tissue environment. They could also take on a proinflammatory phenotype in certain conditions. KEY MESSAGES Treg cells perform distinct functions, including the induction of immune tolerance, suppression of inflammation, and promotion of tissue repair. Subsets of Treg cells in mucosal tissues are regulated by their differentiation stage and tissue inflammatory milieu. Treg cell dysfunction likely plays roles in persistent immune responses and tissue inflammation in asthma and allergic diseases.
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Affiliation(s)
- Min-Jhen Jheng
- Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic Arizona, Scottsdale, AZ
| | - Hirohito Kita
- Division of Allergy, Asthma, and Clinical Immunology, Mayo Clinic Arizona, Scottsdale, AZ
- Department of Immunology, Mayo Clinic Arizona, Scottsdale, AZ
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