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Raoufi A, Soleimani Samarkhazan H, Nouri S, Khaksari MN, Abbasi Sourki P, Sargazi Aval O, Baradaran B, Aghaei M. Macrophages in graft-versus-host disease (GVHD): dual roles as therapeutic tools and targets. Clin Exp Med 2025; 25:73. [PMID: 40048037 PMCID: PMC11885342 DOI: 10.1007/s10238-025-01588-0] [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: 12/27/2024] [Accepted: 02/03/2025] [Indexed: 03/09/2025]
Abstract
Graft-versus-host disease remains one of the most formidable barriers to the complete success of hematopoietic stem cell transplantation that has emerged as the curative approach for many hematopoietic malignancies because it affects quality of life and overall survival. Macrophages are among the important members of the immune system, which perform dual roles in GVHD as both therapeutic tools and targets. This review epitomizes the multifunctional role of macrophages in the pathophysiology of both acute and chronic GVHD. Macrophages play an important role in the early phase of GVHD because of their recruitment and infiltration into target organs. Furthermore, they polarize into two functionally different phenotypes, including M1 and M2. In the case of acute GVHD, most macrophages express the M1 phenotype characterized by the production of pro-inflammatory cytokines that contribute to tissue damage. In contrast, in chronic GVHD, macrophages tend toward the M2 phenotype associated with the repair of tissues and fibrosis. A critical balance among these phenotypes is central to the course and severity of GVHD. Further interactions of macrophages with other lymphocytes such as T cells, B cells, and fibroblast further determine the course of GVHD. Macrophage interaction associated with alloreactive T cells promotes inflammation. This is therefore important in inducing injuries of tissues during acute GVHD. Interaction of macrophages, B cell, fibroblast, and CD4+ T cells promotes fibrosis during chronic GVHD and, hence, the subsequent dysfunction of organs. These are some insights, while several challenges remain. First, the impact of the dominant cytokines in GVHD on the polarization of macrophages is incompletely characterized and sometimes controversial. Second, the development of targeted therapies able to modulate macrophage function without systemic side effects remains an area of ongoing investigation. Future directions involve the exploration of macrophage-targeted therapies, including small molecules, antibodies, and nanotechnology, which modulate macrophage behavior and improve patient outcomes. This underlines the fact that a profound understanding of the dual role of macrophages in GVHD is essential for developing new and more effective therapeutic strategies. Targeting macrophages might represent one avenue for decreasing the incidence and severity of GVHD and improving the success and safety of HSCT.
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Affiliation(s)
- Atieh Raoufi
- Department of Immunology, Student Research Committee, School of Medicine, Zanjan University of Medical Science, Zanjan, Iran
| | - Hamed Soleimani Samarkhazan
- Student Research Committee, Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sina Nouri
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Mohammad Navid Khaksari
- Department of Hematology and Blood Banking, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Parvaneh Abbasi Sourki
- Department of Hematology, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
| | - Omolbanin Sargazi Aval
- Department of Hematology, Faculty of Allied Medical Sciences, Zabol University of Medical Sciences, Zabol, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Daneshghah Ave, Tabriz, Iran.
| | - Mojtaba Aghaei
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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McManus D, Copsel SN, Pffeifer BJ, Wolf D, Barreras H, Ma S, Khodor A, Komai S, Burgos da Silva M, Hazime H, Gallardo M, van den Brink MR, Abreu MT, Hill GR, Perez VL, Levy RB. Pretransplant targeting of TNFRSF25 and CD25 stimulates recipient Tregs in target tissues ameliorating GVHD post-HSCT. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.16.633453. [PMID: 39896683 PMCID: PMC11785081 DOI: 10.1101/2025.01.16.633453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
The current approach to minimize transplant-associated complications, including graft-versus-host disease (GVHD) includes long-term pharmacological immune suppression frequently accompanied by unwanted side effects. Advances in targeted immunotherapies regulating alloantigen responses in the recipient continue to reduce the need for pan-immunosuppression. Here, in vivo targeting of the TNF superfamily receptor 25 (TNFRSF25) and the high affinity IL-2 receptor with a TL1A-Ig fusion protein and low dose IL-2, respectively, was used to pretreat recipient mice prior to allogeneic-HSCT (aHSCT). Pretreatment induced Treg expansion persisting early post-aHSCT leading to diminished GVHD and improved transplant outcomes. Expansion was accompanied by an increase in frequency of stable and functionally active Tregs as evidenced by in vitro assays using cells from major GVHD target tissues including colon, liver, and eye. Importantly, pretreatment supported epithelial cell function/integrity, a diverse microbiome including reduction of pathologic bacteria overgrowth and promotion of butyrate producing bacteria, while maintaining physiologic levels of obligate/facultative anaerobes. Notably, using a sphingosine 1-phosphate receptor agonist to sequester T cells in lymphoid tissues, we found that the increased tissue Treg frequency included resident CD69 + CD103 + FoxP3 + hepatic Tregs. In contrast to infusion of donor Treg cells, the strategy developed here resulted in the presence of immunosuppressive target tissue environments in the recipient prior to the receipt of donor allo-reactive T cells and successful perseveration of GVL responses. We posit strategies that circumvent the need of producing large numbers of ex-vivo manipulated Tregs, may be accomplished through in vivo recipient Treg expansion, providing translational approaches to improve aHSCT outcomes.
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Huang Q, Jiang X, Wang B, Wu Z, Zhang F, Huang XJ, Guo H. Gallic acid enhances GVL effects of T cells without exacerbating GVHD after haematopoietic stem cell transplantation. Br J Haematol 2025; 206:120-132. [PMID: 39472128 DOI: 10.1111/bjh.19863] [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: 08/04/2024] [Accepted: 10/16/2024] [Indexed: 01/19/2025]
Abstract
Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is an effective therapy for acute myeloid leukaemia (AML), predominantly due to its potent graft-versus-leukaemia (GVL) effect. However, leukaemia relapse remains a major obstacle to the success of allo-HSCT. In this study, we demonstrated that gallic acid (GA), a natural dietary compound, can enhance T-cell-mediated GVL effects both in vitro and in vivo. GA-treated T cells exhibited increased activation and elevated secretion of cytotoxic cytokines, leading to the apoptosis of AML cells in co-culture systems in vitro. In a non-irradiated leukaemia mouse model, we showed that GA treatment prolonged the survival of leukaemic mice and reduced leukaemia cell infiltration. Further analysis revealed that GA treatment increased T-cell activation and tumour necrosis factor-α secretion. Moreover, integrated transcriptomic and proteomic analyses indicated that GA augments T-cell-mediated GVL effects through the activation of the MAPK and NF-κB pathways. Blocking these pathways individually diminished the protective effect of GA in AML model mice. Importantly, GA administration did not accelerate graft-versus-host disease (GVHD) progression in a mouse model. In conclusion, our study revealed that GA can enhance the GVL effects of T cells without exacerbating GVHD, offering insights into its potential to improve outcomes for patients after HSCT.
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Affiliation(s)
- Qianqian Huang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Xinya Jiang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Bixia Wang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
| | - Zhigui Wu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Fangqing Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Xiao-Jun Huang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
- Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Chinese Academy of Medical Sciences, Beijing, China
| | - Huidong Guo
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing, China
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Blinova VG, Zhdanov DD. Many Faces of Regulatory T Cells: Heterogeneity or Plasticity? Cells 2024; 13:959. [PMID: 38891091 PMCID: PMC11171907 DOI: 10.3390/cells13110959] [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: 04/23/2024] [Revised: 05/21/2024] [Accepted: 05/22/2024] [Indexed: 06/21/2024] Open
Abstract
Regulatory T cells (Tregs) are essential for maintaining the immune balance in normal and pathological conditions. In autoimmune diseases and transplantation, they restrain the loss of self-tolerance and promote engraftment, whereas in cancer, an increase in Treg numbers is mostly associated with tumor growth and poor prognosis. Numerous markers and their combinations have been used to identify Treg subsets, demonstrating the phenotypic diversity of Tregs. The complexity of Treg identification can be hampered by the unstable expression of some markers, the decrease in the expression of a specific marker over time or the emergence of a new marker. It remains unclear whether such phenotypic shifts are due to new conditions or whether the observed changes are due to initially different populations. In the first case, cellular plasticity is observed, whereas in the second, cellular heterogeneity is observed. The difference between these terms in relation to Tregs is rather blurred. Considering the promising perspectives of Tregs in regenerative cell-based therapy, the existing confusing data on Treg phenotypes require further investigation and analysis. In our review, we introduce criteria that allow us to distinguish between the heterogeneity and plasticity of Tregs normally and pathologically, taking a closer look at their diversity and drawing the line between two terms.
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Affiliation(s)
- Varvara G. Blinova
- Laboratory of Medical Biotechnology, Institute of Biomedical Chemistry, Pogodinskaya st. 10/8, 119121 Moscow, Russia;
| | - Dmitry D. Zhdanov
- Laboratory of Medical Biotechnology, Institute of Biomedical Chemistry, Pogodinskaya st. 10/8, 119121 Moscow, Russia;
- Department of Biochemistry, People’s Friendship University of Russia Named after Patrice Lumumba (RUDN University), Miklukho-Maklaya st. 6, 117198 Moscow, Russia
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Wang B, Yu Z, Liu J, Tian Y, Ruan Y, Kong T, Hou M, Yu B, Ling S, Wang D, Chen Y, Xu Y, Deng W, Liang Y. IL-4-induced decrease in both the number and CTLA-4 expression of T reg impairs suppression of Th2 type inflammation in severe atopic dermatitis. J Dermatol Sci 2024; 114:54-63. [PMID: 38556434 DOI: 10.1016/j.jdermsci.2024.03.007] [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: 12/19/2023] [Revised: 02/14/2024] [Accepted: 03/21/2024] [Indexed: 04/02/2024]
Abstract
BACKGROUND Treg plays a pivotal role in the suppression of Th2 cell and the maintenance of immune homeostasis. The precise molecular mechanism underlying the disruption of Treg suppression of Th2 cell and the promotion of Th2 type inflammation in allergic diseases remains elusive. OBJECTIVE This study aims to investigate the molecular mechanism underlying quantitative and functional changes of Treg in AD. METHODS The molecular mechanism was investigated using flow cytometry, mRNA sequencing, co-culture experiments, co-immunoprecipitation, chromatin immunoprecipitation, and bisulfite sequencing in vitro or in AD mice model and patients with AD. RESULTS Increased proportion of Treg was detected in mild and moderate AD. Conversely, characteristic decrease in both the number and CTLA-4 expression of Treg was relevant to serum IL-4 level in severe AD patients, which was verified under a high concentration of IL-4 treatment in vitro. The underlying mechanism is that IL-4/pSTAT6 pathway recruits DNMT1 and HDAC2 to inhibit transcriptional regulation of Foxp3 and CTLA-4 loci. High level of IL-4 impaired the suppression of Treg against Th2 cell differentiation mediated by CTLA-4, and blockade of IL-4Rα signaling in Treg restored Treg number and suppression of Th2 cell in AD model mice and patients with AD. CONCLUSION The number of Treg is relevant to stratification of severity and serum IL-4 level in patients with AD. Abnormal high level of IL-4 epigenetically triggers a decrease in both the number and CTLA-4 expression of Treg. The reduced expression of CTLA-4 on Treg induced by IL-4 impairs suppression of Th2 cell differentiation.
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Affiliation(s)
- Bocheng Wang
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China; Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Zhiying Yu
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China; Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Jiao Liu
- Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Yuyang Tian
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China; Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Yijia Ruan
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China; Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Tinghui Kong
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China; Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Mingjun Hou
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China; Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Bihui Yu
- Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Shiqi Ling
- Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Di Wang
- Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Yishan Chen
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China; Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Yingping Xu
- Experimental Research Center, Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Weiwei Deng
- Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, China.
| | - Yunsheng Liang
- Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, China.
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6
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Pacini CP, Soares MVD, Lacerda JF. The impact of regulatory T cells on the graft-versus-leukemia effect. Front Immunol 2024; 15:1339318. [PMID: 38711496 PMCID: PMC11070504 DOI: 10.3389/fimmu.2024.1339318] [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: 11/15/2023] [Accepted: 04/08/2024] [Indexed: 05/08/2024] Open
Abstract
Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) is the only curative therapy for many hematologic malignancies, whereby the Graft-versus-Leukemia (GVL) effect plays a pivotal role in controlling relapse. However, the success of GVL is hindered by Graft-versus-Host Disease (GVHD), where donor T cells attack healthy tissues in the recipient. The ability of natural regulatory T cells (Treg) to suppress immune responses has been exploited as a therapeutical option against GVHD. Still, it is crucial to evaluate if the ability of Treg to suppress GVHD does not compromise the benefits of GVL. Initial studies in animal models suggest that Treg can attenuate GVHD while preserving GVL, but results vary according to tumor type. Human trials using Treg as GVHD prophylaxis or treatment show promising results, emphasizing the importance of infusion timing and Treg/Tcon ratios. In this review, we discuss strategies that can be used aiming to enhance GVL post-Treg infusion and the proposed mechanisms for the maintenance of the GVL effect upon the adoptive Treg transfer. In order to optimize the therapeutic outcomes of Treg administration in allo-HSCT, future efforts should focus on refining Treg sources for infusion and evaluating their specificity for antigens mediating GVHD while preserving GVL responses.
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Affiliation(s)
- Carolina P. Pacini
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Maria V. D. Soares
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - João F. Lacerda
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
- Serviço de Hematologia e Transplantação de Medula, Hospital de Santa Maria, ULS Santa Maria, Lisbon, Portugal
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7
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Brunner TM, Serve S, Marx AF, Fadejeva J, Saikali P, Dzamukova M, Durán-Hernández N, Kommer C, Heinrich F, Durek P, Heinz GA, Höfer T, Mashreghi MF, Kühn R, Pinschewer DD, Löhning M. A type 1 immunity-restricted promoter of the IL-33 receptor gene directs antiviral T-cell responses. Nat Immunol 2024; 25:256-267. [PMID: 38172258 PMCID: PMC10834369 DOI: 10.1038/s41590-023-01697-6] [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: 01/24/2023] [Accepted: 11/02/2023] [Indexed: 01/05/2024]
Abstract
The pleiotropic alarmin interleukin-33 (IL-33) drives type 1, type 2 and regulatory T-cell responses via its receptor ST2. Subset-specific differences in ST2 expression intensity and dynamics suggest that transcriptional regulation is key in orchestrating the context-dependent activity of IL-33-ST2 signaling in T-cell immunity. Here, we identify a previously unrecognized alternative promoter in mice and humans that is located far upstream of the curated ST2-coding gene and drives ST2 expression in type 1 immunity. Mice lacking this promoter exhibit a selective loss of ST2 expression in type 1- but not type 2-biased T cells, resulting in impaired expansion of cytotoxic T cells (CTLs) and T-helper 1 cells upon viral infection. T-cell-intrinsic IL-33 signaling via type 1 promoter-driven ST2 is critical to generate a clonally diverse population of antiviral short-lived effector CTLs. Thus, lineage-specific alternative promoter usage directs alarmin responsiveness in T-cell subsets and offers opportunities for immune cell-specific targeting of the IL-33-ST2 axis in infections and inflammatory diseases.
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Affiliation(s)
- Tobias M Brunner
- Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
- Pitzer Laboratory of Osteoarthritis Research, German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany.
| | - Sebastian Serve
- Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Pitzer Laboratory of Osteoarthritis Research, German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, Berlin, Germany
| | - Anna-Friederike Marx
- Division of Experimental Virology, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Jelizaveta Fadejeva
- Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Pitzer Laboratory of Osteoarthritis Research, German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany
| | - Philippe Saikali
- Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Pitzer Laboratory of Osteoarthritis Research, German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany
| | - Maria Dzamukova
- Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Pitzer Laboratory of Osteoarthritis Research, German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany
| | - Nayar Durán-Hernández
- Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Pitzer Laboratory of Osteoarthritis Research, German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany
| | - Christoph Kommer
- Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- BioQuant Center, University of Heidelberg, Heidelberg, Germany
| | - Frederik Heinrich
- Therapeutic Gene Regulation, German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany
| | - Pawel Durek
- Therapeutic Gene Regulation, German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany
| | - Gitta A Heinz
- Therapeutic Gene Regulation, German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany
| | - Thomas Höfer
- Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- BioQuant Center, University of Heidelberg, Heidelberg, Germany
| | - Mir-Farzin Mashreghi
- Therapeutic Gene Regulation, German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany
| | - Ralf Kühn
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Daniel D Pinschewer
- Division of Experimental Virology, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Max Löhning
- Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
- Pitzer Laboratory of Osteoarthritis Research, German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany.
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8
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Cassano A, Chong AS, Alegre ML. Tregs in transplantation tolerance: role and therapeutic potential. FRONTIERS IN TRANSPLANTATION 2023; 2:1217065. [PMID: 38993904 PMCID: PMC11235334 DOI: 10.3389/frtra.2023.1217065] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 08/14/2023] [Indexed: 07/13/2024]
Abstract
CD4+ Foxp3+ regulatory T cells (Tregs) are indispensable for preventing autoimmunity, and they play a role in cancer and transplantation settings by restraining immune responses. In this review, we describe evidence for the importance of Tregs in the induction versus maintenance of transplantation tolerance, discussing insights into mechanisms of Treg control of the alloimmune response. Further, we address the therapeutic potential of Tregs as a clinical intervention after transplantation, highlighting engineered CAR-Tregs as well as expansion of donor and host Tregs.
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Affiliation(s)
- Alexandra Cassano
- Department of Medicine, University of Chicago, Chicago, IL, United States
| | - Anita S. Chong
- Department of Surgery, University of Chicago, Chicago, IL, United States
| | - Maria-Luisa Alegre
- Department of Medicine, University of Chicago, Chicago, IL, United States
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9
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Wang S, Zhao X, Wu S, Cui D, Xu Z. Myeloid-derived suppressor cells: key immunosuppressive regulators and therapeutic targets in hematological malignancies. Biomark Res 2023; 11:34. [PMID: 36978204 PMCID: PMC10049909 DOI: 10.1186/s40364-023-00475-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 03/15/2023] [Indexed: 03/30/2023] Open
Abstract
The immunosuppressive tumor microenvironment (TME) supports the development of tumors and limits tumor immunotherapy, including hematological malignancies. Hematological malignancies remain a major public health issue with high morbidity and mortality worldwide. As an important component of immunosuppressive regulators, the phenotypic characteristics and prognostic value of myeloid-derived suppressor cells (MDSCs) have received much attention. A variety of MDSC-targeting therapeutic approaches have produced encouraging outcomes. However, the use of various MDSC-targeted treatment strategies in hematologic malignancies is still difficult due to the heterogeneity of hematologic malignancies and the complexity of the immune system. In this review, we summarize the biological functions of MDSCs and further provide a summary of the phenotypes and suppressive mechanisms of MDSC populations expanded in various types of hematological malignancy contexts. Moreover, we discussed the clinical correlation between MDSCs and the diagnosis of malignant hematological disease, as well as the drugs targeting MDSCs, and focused on summarizing the therapeutic strategies in combination with other immunotherapies, such as various immune checkpoint inhibitors (ICIs), that are under active investigation. We highlight the new direction of targeting MDSCs to improve the therapeutic efficacy of tumors.
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Affiliation(s)
- Shifen Wang
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xingyun Zhao
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Siwen Wu
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dawei Cui
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Zhenshu Xu
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou, China.
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10
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Mok MY, Law KS, Kong WY, Luo CY, Asfaw ET, Chan KW, Huang FP, Lau CS, Chan GCF. Interleukin-33 Ameliorates Murine Systemic Lupus Erythematosus and Is Associated with Induction of M2 Macrophage Polarisation and Regulatory T Cells. J Innate Immun 2023; 15:485-498. [PMID: 36889298 PMCID: PMC10134067 DOI: 10.1159/000529931] [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: 08/22/2022] [Accepted: 02/14/2023] [Indexed: 03/10/2023] Open
Abstract
The innate cytokine IL-33 is increasingly recognised to possess biological effects on various immune cells. We have previously demonstrated elevated serum level of soluble ST2 in patients with active systemic lupus erythematosus suggesting involvement of IL-33 and its receptor in the lupus pathogenesis. This study sought to examine the effect of exogenous IL-33 on disease activity of pre-disease lupus-prone mice and the underlying cellular mechanisms. Recombinant IL-33 was administered to MRL/lpr mice for 6 weeks, whereas control group received phosphate-buffered saline. IL-33-treated mice displayed less proteinuria, renal histological inflammatory changes, and had lower serum levels of pro-inflammatory cytokines including IL-6 and TNF-α. Renal tissue and splenic CD11b+ extracts showed features of M2 polarisation with elevated mRNA expression of Arg1, FIZZI, and reduced iNOS. These mice also had increased IL-13, ST2, Gata3, and Foxp3 mRNA expression in renal and splenic tissues. Kidneys of these mice displayed less CD11b+ infiltration, had downregulated MCP-1, and increased infiltration of Foxp3-expressing cells. Splenic CD4+ T cells showed increased ST2-expressing CD4+Foxp3+ population and reduced IFN-γ+ population. There were no differences in serum anti-dsDNA antibodies and renal C3 and IgG2a deposit in these mice. Exogenous IL-33 was found to ameliorate disease activity in lupus-prone mice with induction of M2 polarisation, Th2 response, and expansion of regulatory T cells. IL-33 likely orchestrated autoregulation of these cells through upregulation of ST2 expression.
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Affiliation(s)
- Mo Yin Mok
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China
- Department of Medicine, University of Hong Kong, Hong Kong SAR, China
| | - Ka Sin Law
- Department of Medicine, University of Hong Kong, Hong Kong SAR, China
| | - Wing Yin Kong
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China
| | - Cai Yun Luo
- Department of Paediatrics and Adolescent Medicine, University of Hong Kong, Hong Kong SAR, China
| | - Endale T. Asfaw
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China
| | - Kwok Wah Chan
- Department of Pathology, University of Hong Kong, Hong Kong SAR, China
| | - Fang Ping Huang
- Department of Pathology, University of Hong Kong, Hong Kong SAR, China
| | - Chak Sing Lau
- Department of Medicine, University of Hong Kong, Hong Kong SAR, China
| | - Godfrey Chi Fung Chan
- Department of Paediatrics and Adolescent Medicine, University of Hong Kong, Hong Kong SAR, China
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11
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Abstract
When discovered in the early 2000s, interleukin-33 (IL-33) was characterized as a potent driver of type 2 immunity and implicated in parasite clearance, as well as asthma, allergy, and lung fibrosis. Yet research in other models has since revealed that IL-33 is a highly pleiotropic molecule with diverse functions. These activities are supported by elusive release mechanisms and diverse expression of the IL-33 receptor, STimulation 2 (ST2), on both immune and stromal cells. Interestingly, IL-33 also supports type 1 immune responses during viral and tumor immunity and after allogeneic hematopoietic stem cell transplantation. Yet the IL-33-ST2 axis is also critical to the establishment of systemic homeostasis and tissue repair and regeneration. Despite these recent findings, the mechanisms by which IL-33 governs the balance between immunity and homeostasis or can support both effective repair and pathogenic fibrosis are poorly understood. As such, ongoing research is trying to understand the potential reparative and regulatory versus pro-inflammatory and pro-fibrotic roles for IL-33 in transplantation. This review provides an overview of the emerging regenerative role of IL-33 in organ homeostasis and tissue repair as it relates to transplantation immunology. It also outlines the known impacts of IL-33 in commonly transplanted solid organs and covers the envisioned roles for IL-33 in ischemia-reperfusion injury, rejection, and tolerance. Finally, we give a comprehensive summary of its effects on different cell populations involved in these processes, including ST2 + regulatory T cells, innate lymphoid cell type 2, as well as significant myeloid cell populations.
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12
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Shaikh H, Pezoldt J, Mokhtari Z, Gamboa Vargas J, Le DD, Peña Mosca J, Arellano Viera E, Kern MA, Graf C, Beyersdorf N, Lutz MB, Riedel A, Büttner-Herold M, Zernecke A, Einsele H, Saliba AE, Ludewig B, Huehn J, Beilhack A. Fibroblastic reticular cells mitigate acute GvHD via MHCII-dependent maintenance of regulatory T cells. JCI Insight 2022; 7:154250. [PMID: 36227687 DOI: 10.1172/jci.insight.154250] [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: 08/23/2021] [Accepted: 10/07/2022] [Indexed: 12/15/2022] Open
Abstract
Acute graft versus host disease (aGvHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT) inflicted by alloreactive T cells primed in secondary lymphoid organs (SLOs) and subsequent damage to aGvHD target tissues. In recent years, Treg transfer and/or expansion has emerged as a promising therapy to modulate aGvHD. However, cellular niches essential for fostering Tregs to prevent aGvHD have not been explored. Here, we tested whether and to what extent MHC class II (MHCII) expressed on Ccl19+ fibroblastic reticular cells (FRCs) shape the donor CD4+ T cell response during aGvHD. Animals lacking MHCII expression on Ccl19-Cre-expressing FRCs (MHCIIΔCcl19) showed aberrant CD4+ T cell activation in the effector phase, resulting in exacerbated aGvHD that was associated with significantly reduced expansion of Foxp3+ Tregs and invariant NK T (iNKT) cells. Skewed Treg maintenance in MHCIIΔCcl19 mice resulted in loss of protection from aGvHD provided by adoptively transferred donor Tregs. In contrast, although FRCs upregulated costimulatory surface receptors, and although they degraded and processed exogenous antigens after myeloablative irradiation, FRCs were dispensable to activate alloreactive CD4+ T cells in 2 mouse models of aGvHD. In summary, these data reveal an immunoprotective, MHCII-mediated function of FRC niches in secondary lymphoid organs (SLOs) after allo-HCT and highlight a framework of cellular and molecular interactions that regulate CD4+ T cell alloimmunity.
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Affiliation(s)
- Haroon Shaikh
- Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and.,Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.,Graduate School of Life Sciences, Würzburg University, Würzburg, Germany
| | - Joern Pezoldt
- Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.,Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Zeinab Mokhtari
- Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and.,Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany
| | - Juan Gamboa Vargas
- Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and.,Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.,Graduate School of Life Sciences, Würzburg University, Würzburg, Germany
| | - Duc-Dung Le
- Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and.,Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany
| | - Josefina Peña Mosca
- Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and.,Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.,Graduate School of Life Sciences, Würzburg University, Würzburg, Germany
| | - Estibaliz Arellano Viera
- Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and.,Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany
| | - Michael Ag Kern
- Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and.,Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.,Graduate School of Life Sciences, Würzburg University, Würzburg, Germany
| | - Caroline Graf
- Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and.,Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany
| | - Niklas Beyersdorf
- Graduate School of Life Sciences, Würzburg University, Würzburg, Germany.,Institute for Virology and Immunobiology, Würzburg University, Würzburg, Germany
| | - Manfred B Lutz
- Graduate School of Life Sciences, Würzburg University, Würzburg, Germany.,Institute for Virology and Immunobiology, Würzburg University, Würzburg, Germany
| | - Angela Riedel
- Mildred Scheel Early Career Centre, University Hospital of Würzburg, Würzburg, Germany
| | - Maike Büttner-Herold
- Department of Nephropathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Alma Zernecke
- Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
| | - Hermann Einsele
- Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany
| | - Antoine-Emmanuel Saliba
- Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection (HZI), Würzburg, Germany
| | - Burkhard Ludewig
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.,Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Jochen Huehn
- Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.,Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
| | - Andreas Beilhack
- Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and.,Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.,Graduate School of Life Sciences, Würzburg University, Würzburg, Germany
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13
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Guo H, Bossila EA, Ma X, Zhao C, Zhao Y. Dual Immune Regulatory Roles of Interleukin-33 in Pathological Conditions. Cells 2022; 11:cells11203237. [PMID: 36291105 PMCID: PMC9600220 DOI: 10.3390/cells11203237] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 10/07/2022] [Accepted: 10/11/2022] [Indexed: 11/20/2022] Open
Abstract
Interleukin-33 (IL-33), a member of the IL-1 cytokine family and a multifunctional cytokine, plays critical roles in maintaining host homeostasis and in pathological conditions, such as allergy, infectious diseases, and cancer, by acting on multiple types of immune cells and promoting type 1 and 2 immune responses. IL-33 is rapidly released by immune and non-immune cells upon stimulation by stress, acting as an “alarmin” by binding to its receptor, suppression of tumorigenicity 2 (ST2), to trigger downstream signaling pathways and activate inflammatory and immune responses. It has been recognized that IL-33 displays dual-functioning immune regulatory effects in many diseases and has both pro- and anti-tumorigenic effects, likely depending on its primary target cells, IL-33/sST2 expression levels, cellular context, and the cytokine microenvironment. Herein, we summarize our current understanding of the biological functions of IL-33 and its roles in the pathogenesis of various conditions, including inflammatory and autoimmune diseases, infections, cancers, and cases of organ transplantation. We emphasize the nature of context-dependent dual immune regulatory functions of IL-33 in many cells and diseases and review systemic studies to understand the distinct roles of IL-33 in different cells, which is essential to the development of more effective diagnoses and therapeutic approaches for IL-33-related diseases.
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Affiliation(s)
- Han Guo
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101499, China
| | - Elhusseny A. Bossila
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101499, China
- Biotechnology Department, Faculty of Agriculture Al-Azhar University, Cairo 11311, Egypt
| | - Xinran Ma
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101499, China
| | - Chenxu Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101499, China
| | - Yong Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101499, China
- Beijing Institute for Stem Cell and Regeneration, Beijing 100101, China
- Correspondence: ; Tel.: +86-10-64807302; Fax: +86-10-64807313
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14
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Copsel SN, Wolf D, Pfeiffer B, Barreras H, Perez VL, Levy RB. Recipient Tregs: Can They Be Exploited for Successful Hematopoietic Stem Cell Transplant Outcomes? Front Immunol 2022; 13:932527. [PMID: 35799783 PMCID: PMC9253768 DOI: 10.3389/fimmu.2022.932527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 05/18/2022] [Indexed: 02/03/2023] Open
Abstract
Human and mouse CD4+FoxP3+ T cells (Tregs) comprise non-redundant regulatory compartments which maintain self-tolerance and have been found to be of potential therapeutic usefulness in autoimmune disorders and transplants including allogeneic hematopoietic stem cell transplantation (allo-HSCT). There is substantial literature interrogating the application of donor derived Tregs for the prevention of graft versus host disease (GVHD). This Mini-Review will focus on the recipient's Tregs which persist post-transplant. Although treatment in patients with low dose IL-2 months post-HSCT are encouraging, manipulating Tregs in recipients early post-transplant is challenging, in part likely an indirect consequence of damage to the microenvironment required to support Treg expansion of which little is understood. This review will discuss the potential for manipulating recipient Tregs in vivo prior to and after HSCT (fusion proteins, mAbs). Strategies that would circumvent donor/recipient peripheral blood harvest, cell culture and ex-vivo Treg expansion will be considered for the translational application of Tregs to improve HSCT outcomes.
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Affiliation(s)
- Sabrina N. Copsel
- Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL, United States
| | - Dietlinde Wolf
- Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, FL, United States
| | - Brent Pfeiffer
- Department of Pediatrics, University of Miami School of Medicine, Miami, FL, United States
| | - Henry Barreras
- Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL, United States
| | - Victor L. Perez
- Foster Center for Ocular Immunology, Duke Eye Center, Duke University, Durham, NC, United States
| | - Robert B. Levy
- Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL, United States,Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, FL, United States,Department of Ophthalmology, University of Miami School of Medicine, Miami, FL, United States,*Correspondence: Robert B. Levy,
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15
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Dwyer GK, Mathews LR, Villegas JA, Lucas A, Gonzalez de Peredo A, Blazar BR, Girard JP, Poholek AC, Luther SA, Shlomchik W, Turnquist HR. IL-33 acts as a costimulatory signal to generate alloreactive Th1 cells in graft-versus-host disease. J Clin Invest 2022; 132:e150927. [PMID: 35503257 PMCID: PMC9197517 DOI: 10.1172/jci150927] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 04/28/2022] [Indexed: 12/02/2022] Open
Abstract
Antigen-presenting cells (APCs) integrate signals emanating from local pathology and program appropriate T cell responses. In allogeneic hematopoietic stem cell transplantation (alloHCT), recipient conditioning releases damage-associated molecular patterns (DAMPs) that generate proinflammatory APCs that secrete IL-12, which is a driver of donor Th1 responses, causing graft-versus-host disease (GVHD). Nevertheless, other mechanisms exist to initiate alloreactive T cell responses, as recipients with disrupted DAMP signaling or lacking IL-12 develop GVHD. We established that tissue damage signals are perceived directly by donor CD4+ T cells and promoted T cell expansion and differentiation. Specifically, the fibroblastic reticular cell-derived DAMP IL-33 is increased by recipient conditioning and is critical for the initial activation, proliferation, and differentiation of alloreactive Th1 cells. IL-33 stimulation of CD4+ T cells was not required for lymphopenia-induced expansion, however. IL-33 promoted IL-12-independent expression of Tbet and generation of Th1 cells that infiltrated GVHD target tissues. Mechanistically, IL-33 augmented CD4+ T cell TCR-associated signaling pathways in response to alloantigen. This enhanced T cell expansion and Th1 polarization, but inhibited the expression of regulatory molecules such as IL-10 and Foxp3. These data establish an unappreciated role for IL-33 as a costimulatory signal for donor Th1 generation after alloHCT.
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Affiliation(s)
- Gaelen K. Dwyer
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Thomas E. Starzl Transplantation Institute and
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Lisa R. Mathews
- Thomas E. Starzl Transplantation Institute and
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - José A. Villegas
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
| | - Anna Lucas
- Thomas E. Starzl Transplantation Institute and
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Anne Gonzalez de Peredo
- Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, Centre National de la Recherche Scientifique, Université Paul Sabatier, Toulouse, France
| | - Bruce R. Blazar
- Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Jean-Philippe Girard
- Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, Centre National de la Recherche Scientifique, Université Paul Sabatier, Toulouse, France
| | - Amanda C. Poholek
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Division of Pediatric Rheumatology, and
| | - Sanjiv A. Luther
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
| | - Warren Shlomchik
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Thomas E. Starzl Transplantation Institute and
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Hēth R. Turnquist
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Thomas E. Starzl Transplantation Institute and
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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16
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Ferrara J, Prado-Acosta M. Graft-versus-host disease: establishing IL-33 as an important costimulatory molecule. J Clin Invest 2022; 132:160692. [PMID: 35703182 PMCID: PMC9197507 DOI: 10.1172/jci160692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Approximately half of patients with hematologic malignancy who are treated with allogeneic hematopoietic stem cell transplantation (alloHCT) experience graft-versus-host disease (GVHD), which has high mortality rates despite immunosuppressive therapy. IL-12 is known to drive donor T cells toward an inflammatory Th1 lineage in GVHD, but other mechanisms also promote pathological Th1 alloimmune responses. In this issue of the JCI, Dwyer et al. report on their use of transgenic mice and alloHCT models of GVHD to demonstrate that IL-33 acts directly on donor T cells to increase Tbet expression independently of IL-12. Notably, IL-33 amplified T cell receptor–signaling pathways and inhibited production of regulatory molecules. These findings firmly establish IL-33 as an important costimulatory molecule for Th1 cells during GVHD and provide a target for reducing GVHD, especially in the gastrointestinal (GI) tract, where damage drives mortality.
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17
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New insights for regulatory T cell in lupus nephritis. Clin Exp Rheumatol 2022; 21:103134. [PMID: 35690245 DOI: 10.1016/j.autrev.2022.103134] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 06/07/2022] [Indexed: 11/20/2022]
Abstract
Lupus nephritis (LN) is a complicated autoimmune disease marked by out-of-balance of immunological reactivity and immune tolerance. With the advance of immunotherapy in human disease, regulatory T (Treg) cells serve a crucial function in immune tolerance regulation and are characterized with suppression function as one of the most important research hotspots for autoimmunity diseases. In recent years, Treg cells have shown the robust potential for treatment to autoimmunity diseases like type I diabetic mellitus and rheumatoid arthritis. However, Treg cell therapy is poorly understood for LN patients. This review aims to summarize new insights for Treg-targeting techniques in LN patients. The current data regarding the biology features of Treg cells in LN patients is discussed. The propotion of Treg cells in LN patients have contradictory results regarding the use of different molecular markers. Forkhead box protein 3 (FOXP3) are hallmarks for control function of Treg cells. Treg cells can directly or indirectly target T cells and B cells by playing supressive role. The molecular targets for Treg cells in LN patients includes gene variants, miRNAs, and inflammatory related factors. Based on the current knowledge of Treg cell biology, several therapeutic strategies could be used to treat LN: cell transplantation, low dose IL-2 treatment, drugs target the balance of Treg and type 17 T helper (Th17) cells, and Chinese medicine.
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18
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Jiang Z, Zhu H, Wang P, Que W, Zhong L, Li X, Du F. Different subpopulations of regulatory T cells in human autoimmune disease, transplantation, and tumor immunity. MedComm (Beijing) 2022; 3:e137. [PMID: 35474948 PMCID: PMC9023873 DOI: 10.1002/mco2.137] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 04/06/2022] [Accepted: 04/07/2022] [Indexed: 12/11/2022] Open
Abstract
CD4+CD25+ regulatory T cells (Tregs), a subpopulation of naturally CD4+ T cells that characteristically express transcription factor Forkhead box P3 (FOXP3), play a pivotal role in the maintenance of immune homeostasis and the prevention of autoimmunity. With the development of biological technology, the understanding of plasticity and stability of Tregs has been further developed. Recent studies have suggested that human Tregs are functionally and phenotypically diverse. The functions and mechanisms of different phenotypes of Tregs in different disease settings, such as tumor microenvironment, autoimmune diseases, and transplantation, have gradually become hot spots of immunology research that arouse extensive attention. Among the complex functions, CD4+CD25+FOXP3+ Tregs possess a potent immunosuppressive capacity and can produce various cytokines, such as IL‐2, IL‐10, and TGF‐β, to regulate immune homeostasis. They can alleviate the progression of diseases by resisting inflammatory immune responses, whereas promoting the poor prognosis of diseases by helping cells evade immune surveillance or suppressing effector T cells activity. Therefore, methods for targeting Tregs to regulate their functions in the immune microenvironment, such as depleting them to strengthen tumor immunity or expanding them to treat immunological diseases, need to be developed. Here, we discuss that different subpopulations of Tregs are essential for the development of immunotherapeutic strategies involving Tregs in human diseases.
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Affiliation(s)
- Zhongyi Jiang
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
| | - Haitao Zhu
- Department of Hepatobiliary Surgery The Affiliated Hospital of Guizhou Medical University Guizhou P. R. China
| | - Pusen Wang
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
| | - Weitao Que
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
| | - Lin Zhong
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
| | - Xiao‐Kang Li
- Department of General Surgery Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai P. R. China
- Division of Transplantation Immunology National Research Institute for Child Health and Development Tokyo Japan
| | - Futian Du
- Department of Hepatobiliary Surgery Weifang People's Hospital Shandong P. R. China
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19
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Sarrand J, Soyfoo M. Involvement of IL-33 in the Pathophysiology of Systemic Lupus Erythematosus: Review. Int J Mol Sci 2022; 23:ijms23063138. [PMID: 35328556 PMCID: PMC8949418 DOI: 10.3390/ijms23063138] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/08/2022] [Accepted: 03/10/2022] [Indexed: 02/01/2023] Open
Abstract
IL-33 is a newly discovered cytokine displaying pleiotropic localizations and functions. More specifically, it also functions as an alarmin, following its release from cells undergoing cell death or necrosis, to alert the innate immune system. The role of IL-33 has been underlined in several inflammatory and autoimmune diseases including systemic lupus erythematosus (SLE). The expressions of IL-33 as well as its receptor, ST2, are significantly upregulated in SLE patients and in patients with lupus nephritis. This review discusses the involvement of IL-33 in the pathology of SLE.
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20
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A biomarker panel for risk of early respiratory failure following hematopoietic cell transplantation. Blood Adv 2022; 6:1866-1878. [PMID: 35139145 PMCID: PMC8941462 DOI: 10.1182/bloodadvances.2021005770] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 01/22/2022] [Indexed: 11/20/2022] Open
Abstract
This study identified and validated ST2, WFDC2, IL-6, and TNFR1 as risk biomarkers for RF and related mortality post-HCT. Plasma biomarkers associated with respiratory failure (RF) following hematopoietic cell transplantation (HCT) have not been identified. Therefore, we aimed to validate early (7 and 14 days post-HCT) risk biomarkers for RF. Using tandem mass spectrometry, we compared plasma obtained at day 14 post-HCT from 15 patients with RF and 15 patients without RF. Six candidate proteins, from this discovery cohort or identified in the literature, were measured by enzyme-linked immunosorbent assay in day-7 and day-14 post-HCT samples from the training (n = 213) and validation (n = 119) cohorts. Cox proportional-hazard analyses with biomarkers dichotomized by Youden’s index, as well as landmark analyses to determine the association between biomarkers and RF, were performed. Of the 6 markers, Stimulation-2 (ST2), WAP 4-disulfide core domain protein 2 (WFDC2), interleukin-6 (IL-6), and tumor necrosis factor receptor 1 (TNFR1), measured at day 14 post-HCT, had the most significant association with an increased risk for RF in the training cohort (ST2: hazard ratio [HR], 4.5, P = .004; WFDC2: HR, 4.2, P = .010; IL-6: HR, 6.9, P < .001; and TFNR1: HR, 6.1, P < .001) and in the validation cohort (ST2: HR, 23.2, P = .013; WFDC2: HR, 18.2, P = .019; IL-6: HR, 12.2, P = .014; and TFNR1: HR, 16.1, P = .001) after adjusting for the conditioning regimen. Using cause-specific landmark analyses, including days 7 and 14, high plasma levels of ST2, WFDC2, IL-6, and TNFR1 were associated with an increased HR for RF in the training and validation cohorts. These biomarkers were also predictive of mortality from RF. ST2, WFDC2, IL-6 and TNFR1 levels measured early posttransplantation improve risk stratification for RF and its related mortality.
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21
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Abstract
Our understanding of the functions of the IL-1 superfamily cytokine and damage-associated molecular pattern IL-33 continues to evolve with our understanding of homeostasis and immunity. The early findings that IL-33 is a potent driver of type 2 immune responses promoting parasite expulsion, but also inflammatory diseases like allergy and asthma, have been further supported. Yet, as the importance of a type 2 response in tissue repair and homeostasis has emerged, so has the fundamental importance of IL-33 to these processes. In this review, we outline an evolving understanding of IL-33 immunobiology, paying particular attention to how IL-33 directs a network of ST2+ regulatory T cells, reparative and regulatory macrophages, and type 2 innate lymphoid cells that are fundamental to tissue development, homeostasis, and repair. Expected final online publication date for the Annual Review of Immunology, Volume 40 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Gaelen K. Dwyer
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Louise M. D'Cruz
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Hēth R. Turnquist
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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22
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Rozario C, Martínez-Sobrido L, McSorley HJ, Chauché C. Could Interleukin-33 (IL-33) Govern the Outcome of an Equine Influenza Virus Infection? Learning from Other Species. Viruses 2021; 13:2519. [PMID: 34960788 PMCID: PMC8704309 DOI: 10.3390/v13122519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/04/2021] [Accepted: 12/13/2021] [Indexed: 11/16/2022] Open
Abstract
Influenza A viruses (IAVs) are important respiratory pathogens of horses and humans. Infected individuals develop typical respiratory disorders associated with the death of airway epithelial cells (AECs) in infected areas. Virulence and risk of secondary bacterial infections vary among IAV strains. The IAV non-structural proteins, NS1, PB1-F2, and PA-X are important virulence factors controlling AEC death and host immune responses to viral and bacterial infection. Polymorphism in these proteins impacts their function. Evidence from human and mouse studies indicates that upon IAV infection, the manner of AEC death impacts disease severity. Indeed, while apoptosis is considered anti-inflammatory, necrosis is thought to cause pulmonary damage with the release of damage-associated molecular patterns (DAMPs), such as interleukin-33 (IL-33). IL-33 is a potent inflammatory mediator released by necrotic cells, playing a crucial role in anti-viral and anti-bacterial immunity. Here, we discuss studies in human and murine models which investigate how viral determinants and host immune responses control AEC death and subsequent lung IL-33 release, impacting IAV disease severity. Confirming such data in horses and improving our understanding of early immunologic responses initiated by AEC death during IAV infection will better inform the development of novel therapeutic or vaccine strategies designed to protect life-long lung health in horses and humans, following a One Health approach.
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Affiliation(s)
- Christoforos Rozario
- Centre for Inflammation Research, The Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh BioQuarter, Edinburgh EH16 4TJ, UK;
| | | | - Henry J. McSorley
- Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Wellcome Trust Building, Dow Street, Dundee DD1 5EH, UK;
| | - Caroline Chauché
- Centre for Inflammation Research, The Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh BioQuarter, Edinburgh EH16 4TJ, UK;
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23
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Wang Y. Mesenchymal stem cells (MSC) delays the occurrence of graft-versus-host disease(GVHD) in the inhibition of hematopoietic stem cells in major histocompatibility complex semi-consistent mice by regulating the expression of IFN-γ/IL-6. Bioengineered 2021; 12:4500-4507. [PMID: 34308757 PMCID: PMC8806439 DOI: 10.1080/21655979.2021.1955549] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 07/09/2021] [Indexed: 12/03/2022] Open
Abstract
In recent years, because of its low immunogenicity and immunosuppression, mesenchymal stem cells (MSCs) have become a potential cell therapy for Graft-versus-host disease (GVHD). However, many experiments now focus on the interference of MSCs on T-cell proliferation in vitro and the prevention of GVHD in vivo. However, whether MSCs can effectively treat GVHD, the timing and conditions of treatment are not systematically studied. In order to clarify the therapeutic effect of MSC on GVHD, In this paper, mice were selected to build a model for study, and group control method was used. Experimental research proved that four mice died after transplantation with allogeneic hematopoietic stem cells treated by IFN- γ, and their white blood cell number remained basically unchanged, and their weight changed slightly. In addition, three groups of mice after allogeneic hematopoietic stem cell transplantation were used the incidence of GVHD was X2 = 20.6, indicating that the incidence of GVHD was significantly reduced and the survival rate of mice was significantly increased.
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Affiliation(s)
- Ying Wang
- Department of Hematology, the Seventh Affiliated Hopital, Sun Yat-sen University, Shenzhen, China
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24
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Zaini A, Fulford TS, Grumont RJ, Runting J, Rodrigues G, Ng J, Gerondakis S, Zaph C, Scheer S. c-Rel Is Required for IL-33-Dependent Activation of ILC2s. Front Immunol 2021; 12:667922. [PMID: 34194431 PMCID: PMC8236704 DOI: 10.3389/fimmu.2021.667922] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 05/19/2021] [Indexed: 11/22/2022] Open
Abstract
Group 2 innate lymphoid cells (ILC2s) are emerging as important cellular regulators of homeostatic and disease-associated immune processes. The cytokine interleukin-33 (IL-33) promotes ILC2-dependent inflammation and immunity, with IL-33 having been shown to activate NF-κB in a wide variety of cell types. However, it is currently unclear which NF-κB members play an important role in IL-33-dependent ILC2 biology. Here, we identify the NF-κB family member c-Rel as a critical component of the IL-33-dependent activation of ILC2s. Although c-Rel is dispensable for ILC2 development, it is critical for ILC2 function in the lung, with c-Rel-deficient (c-Rel-/- ) mice present a significantly reduced response to papain- and IL-33-induced lung inflammation. We also show that the absence of c-Rel reduces the IL-33-dependent expansion of ILC2 precursors and lower levels of IL-5 and IL-13 cytokine production by mature ILC2s in the lung. Together, these results identify the IL-33-c-Rel axis as a central control point of ILC2 activation and function.
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Affiliation(s)
- Aidil Zaini
- Infection and Immunity Program, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
| | - Thomas S. Fulford
- Department of Microbiology and Immunology, University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
| | - Raelene J. Grumont
- Infection and Immunity Program, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
| | - Jessica Runting
- Infection and Immunity Program, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
| | - Grace Rodrigues
- Infection and Immunity Program, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
| | - Judy Ng
- Infection and Immunity Program, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
| | - Steve Gerondakis
- Infection and Immunity Program, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
| | - Colby Zaph
- Infection and Immunity Program, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
| | - Sebastian Scheer
- Infection and Immunity Program, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
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25
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Liu O, Xu J, Wang F, Jin W, Zanvit P, Wang D, Goldberg N, Cain A, Guo N, Han Y, Bynum A, Ma G, Wang S, Tang Z, Chen W. Adipose-mesenchymal stromal cells suppress experimental Sjögren syndrome by IL-33-driven expansion of ST2 + regulatory T cells. iScience 2021; 24:102446. [PMID: 33997712 PMCID: PMC8105666 DOI: 10.1016/j.isci.2021.102446] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 03/11/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Adipose-derived mesenchymal stromal cells (ADSCs) play important roles in the alleviation of inflammation and autoimmune diseases. Interleukin-33 (IL-33), a member of the IL-1 family, has been shown to regulate innate and adaptive immunity. However, it is still unknown whether ADSCs regulate immune responses via IL-33. We show here that ADSCs produced IL-33 in response to IL-1β stimulation, which depended on TAK1, ERK, and p38 pathways. ADSCs-derived IL-33 drove the proliferation of CD4+Foxp3+ST2+ regulatory T cells (Tregs) and alleviated experimental autoimmune Sjögren syndrome in mice. Importantly, human ADSCs also produced IL-33 in response to IL-1β. Thus, we have revealed a previously unrecognized immunoregulatory function of ADSCs by IL-33 production in experimental autoimmunity, which may have clinical applications for human immunopathology.
Human and mouse ADSCs express IL-33 in response to IL-β stimulation mADSC-derived IL-33 inhibits inflammation in salivary glands in SS model mADSC-derived IL-33 expand ST2+ Tregs in vitro and in SS model
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Affiliation(s)
- Ousheng Liu
- Mucosal Immunology Section, NIDCR, NIH, Bethesda, MD 20892, USA
- Hunan Key Laboratory of Oral Health Research & Hunan 3D Printing Engineering Research Center of Oral Care & Hunan Clinical Research Center of Oral Major Diseases and Oral Health & Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha 410008, China
| | - Junji Xu
- Mucosal Immunology Section, NIDCR, NIH, Bethesda, MD 20892, USA
| | - Fu Wang
- Mucosal Immunology Section, NIDCR, NIH, Bethesda, MD 20892, USA
- Dalian Medical University, School of Stomatology, Dalian 116044, China
| | - Wenwen Jin
- Mucosal Immunology Section, NIDCR, NIH, Bethesda, MD 20892, USA
| | - Peter Zanvit
- Mucosal Immunology Section, NIDCR, NIH, Bethesda, MD 20892, USA
| | - Dandan Wang
- Mucosal Immunology Section, NIDCR, NIH, Bethesda, MD 20892, USA
| | - Nathan Goldberg
- Mucosal Immunology Section, NIDCR, NIH, Bethesda, MD 20892, USA
| | - Alexander Cain
- Mucosal Immunology Section, NIDCR, NIH, Bethesda, MD 20892, USA
| | - Nancy Guo
- Mucosal Immunology Section, NIDCR, NIH, Bethesda, MD 20892, USA
| | - Yichen Han
- Mucosal Immunology Section, NIDCR, NIH, Bethesda, MD 20892, USA
| | - Andrew Bynum
- Mucosal Immunology Section, NIDCR, NIH, Bethesda, MD 20892, USA
| | - Guowu Ma
- Dalian Medical University, School of Stomatology, Dalian 116044, China
| | - Songlin Wang
- Molecular Laboratory for Gene Therapy and Tooth Regeneration, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing 100050, China
| | - Zhangui Tang
- Hunan Key Laboratory of Oral Health Research & Hunan 3D Printing Engineering Research Center of Oral Care & Hunan Clinical Research Center of Oral Major Diseases and Oral Health & Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha 410008, China
| | - Wanjun Chen
- Mucosal Immunology Section, NIDCR, NIH, Bethesda, MD 20892, USA
- Corresponding author
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26
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Kawai K, Uchiyama M, Hester J, Issa F. IL-33 drives the production of mouse regulatory T cells with enhanced in vivo suppressive activity in skin transplantation. Am J Transplant 2021; 21:978-992. [PMID: 33314772 PMCID: PMC7613121 DOI: 10.1111/ajt.16266] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 07/20/2020] [Accepted: 08/08/2020] [Indexed: 01/25/2023]
Abstract
Regulatory T cells (Tregs) are crucial mediators of immune homeostasis with the ability to modulate allogeneic response and control transplant rejection. Although Treg-based cell therapies have shown immense promise, methods to optimize current strategies are critical for successful implementation within the clinic. IL-33 is a cytokine with pleiotropic properties and effects on Treg function and development. In this study, we explored the unique properties of Treg populations activated through the IL-33/ST2 pathway, aiming to exploit their tolerogenic properties for cell therapy. We show that treatment with exogenous IL-33 results in a generalized downregulation of genes critical to T cell biology together with an upregulation of Treg-associated genes. Tregs that develop in response to IL-33 upregulate critical Treg-associated markers, yet without developing enhanced in vitro suppressive capacity. Conversely, these Tregs display potent regulatory activity in vivo, promoting long-term skin allograft survival in a stringent transplantation model. Detailed transcriptomic and immunophenotypic analyses of IL-33-expanded Tregs reveal an enhancement in graft-homing chemokine receptors, which may be partly responsible for their superior in vivo activity that is not reflected in vitro. IL-33 treatment is therefore an attractive adjunctive strategy for patients receiving Treg cell therapeutics.
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Affiliation(s)
- Kento Kawai
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Masateru Uchiyama
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK,Department of Surgery, Teikyo University, Tokyo, Japan
| | - Joanna Hester
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Fadi Issa
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
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27
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Dwyer GK, Turnquist HR. Untangling Local Pro-Inflammatory, Reparative, and Regulatory Damage-Associated Molecular-Patterns (DAMPs) Pathways to Improve Transplant Outcomes. Front Immunol 2021; 12:611910. [PMID: 33708206 PMCID: PMC7940545 DOI: 10.3389/fimmu.2021.611910] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 01/05/2021] [Indexed: 12/28/2022] Open
Abstract
Detrimental inflammatory responses after solid organ transplantation are initiated when immune cells sense pathogen-associated molecular patterns (PAMPs) and certain damage-associated molecular patterns (DAMPs) released or exposed during transplant-associated processes, such as ischemia/reperfusion injury (IRI), surgical trauma, and recipient conditioning. These inflammatory responses initiate and propagate anti-alloantigen (AlloAg) responses and targeting DAMPs and PAMPs, or the signaling cascades they activate, reduce alloimmunity, and contribute to improved outcomes after allogeneic solid organ transplantation in experimental studies. However, DAMPs have also been implicated in initiating essential anti-inflammatory and reparative functions of specific immune cells, particularly Treg and macrophages. Interestingly, DAMP signaling is also involved in local and systemic homeostasis. Herein, we describe the emerging literature defining how poor outcomes after transplantation may result, not from just an over-abundance of DAMP-driven inflammation, but instead an inadequate presence of a subset of DAMPs or related molecules needed to repair tissue successfully or re-establish tissue homeostasis. Adverse outcomes may also arise when these homeostatic or reparative signals become dysregulated or hijacked by alloreactive immune cells in transplant niches. A complete understanding of the critical pathways controlling tissue repair and homeostasis, and how alloimmune responses or transplant-related processes disrupt these will lead to new immunotherapeutics that can prevent or reverse the tissue pathology leading to lost grafts due to chronic rejection.
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Affiliation(s)
- Gaelen K Dwyer
- Departments of Surgery and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.,Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Hēth R Turnquist
- Departments of Surgery and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.,Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.,McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States
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28
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Peng L, Sun W, Chen L, Wen WP. The Role of Interleukin-33 in Head and Neck Squamous Cell Carcinoma Is Determined by Its Cellular Sources in the Tumor Microenvironment. Front Oncol 2021; 10:588454. [PMID: 33634017 PMCID: PMC7902021 DOI: 10.3389/fonc.2020.588454] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 12/24/2020] [Indexed: 12/09/2022] Open
Abstract
Objectives To investigate the role of interleukin-33 (IL-33) in head and neck squamous cell carcinoma (HNSCC). Materials and Methods RNA-seq data of 520 cases of HNSCC were retrieved from The Cancer Genome Atlas. The tumor microenvironment was deconstructed by xCell using bulk RNA-seq data. The cohort was dichotomized by the median IL-33 expression level. Immune cell components and molecular markers were compared between the high and low IL-33 groups. The prognostic value of IL-33 was evaluated by the log-rank test. Differential gene expression analysis and KEGG pathway enrichment analysis were also conducted. The relationship between the IL-33 expression level and the abundance of its potential cellular sources was evaluated by Pearson’s partial correlation test. Subgroup analysis was conducted in laryngeal, oropharyngeal, and oral cavity squamous cell carcinoma (LSCC, OPSCC, and OCSCC). Results The role of IL-33 in HNSCC was heterogeneous among tumors at different sites. In LSCC, IL-33 may increase the extent of malignancy of tumor cells and act as a pro-tumor factor. In OCSCC, IL-33 may play a role in orchestrating the immune responses against tumor cells and act as an antitumor factor. The role of IL-33 in OPSCC was undetermined. IL-33 in LSCC was mainly derived from endothelial cells, while IL-33 in OCSCC was mainly derived from endothelial and epithelial cells. Conclusion According to the different sources of IL-33 in LSCC and OCSCC, we propose a hypothesis that stroma-derived IL-33 could favor tumor progression, while epithelial-derived IL-33 could favor antitumor immune responses in HNSCC.
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Affiliation(s)
- Liang Peng
- Department of Otolaryngology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Otorhinolaryngology Institute, Sun Yat-sen University, Guangzhou, China
| | - Wei Sun
- Department of Otolaryngology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Otorhinolaryngology Institute, Sun Yat-sen University, Guangzhou, China
| | - Lin Chen
- Department of Otolaryngology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Otorhinolaryngology Institute, Sun Yat-sen University, Guangzhou, China
| | - Wei-Ping Wen
- Department of Otolaryngology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Otorhinolaryngology Institute, Sun Yat-sen University, Guangzhou, China.,Department of Otolaryngology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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29
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Wang Y, Yang Y, Wang M, Wang S, Jeong JM, Xu L, Wen Y, Emontzpohl C, Atkins CL, Duong K, Moreno NF, Yuan X, Hall DR, Dar W, Feng D, Gao B, Xu Y, Czigany Z, Colgan SP, Bynon JS, Akira S, Brown JM, Eltzschig HK, Jacobsen EA, Ju C. Eosinophils attenuate hepatic ischemia-reperfusion injury in mice through ST2-dependent IL-13 production. Sci Transl Med 2021; 13:eabb6576. [PMID: 33536281 PMCID: PMC8167890 DOI: 10.1126/scitranslmed.abb6576] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 09/28/2020] [Accepted: 01/12/2021] [Indexed: 12/14/2022]
Abstract
Eosinophils are a myeloid cell subpopulation that mediates type 2 T helper cell immune responses. Unexpectedly, we identified a rapid accumulation of eosinophils in 22 human liver grafts after hepatic transplantation. In contrast, no eosinophils were detectable in healthy liver tissues before transplantation. Studies with two genetic mouse models of eosinophil deficiency and a mouse model of antibody-mediated eosinophil depletion revealed exacerbated liver injury after hepatic ischemia and reperfusion. Adoptive transfer of bone marrow-derived eosinophils normalized liver injury of eosinophil-deficient mice and reduced hepatic ischemia and reperfusion injury in wild-type mice. Mechanistic studies combining genetic and adoptive transfer approaches identified a critical role of suppression of tumorigenicity (ST2)-dependent production of interleukin-13 by eosinophils in the hepatoprotection against ischemia-reperfusion-induced injury. Together, these data provide insight into a mechanism of eosinophil-mediated liver protection that could serve as a therapeutic target to improve outcomes of patients undergoing liver transplantation.
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Affiliation(s)
- Yaochun Wang
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- Center for Translational Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Yang Yang
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Meng Wang
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Shuhong Wang
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Jong-Min Jeong
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Long Xu
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Yankai Wen
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Christoph Emontzpohl
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Constance Lynn Atkins
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Kevin Duong
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Nicolas F Moreno
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Xiaoyi Yuan
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - David R Hall
- Department of Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Wasim Dar
- Department of Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Dechun Feng
- Laboratory of Liver Disease, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA
| | - Bin Gao
- Laboratory of Liver Disease, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA
| | - Yong Xu
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Zoltan Czigany
- Department of Surgery and Transplantation, Faculty of Medicine, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Sean P Colgan
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - J Steve Bynon
- Department of Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Shizuo Akira
- Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
| | - Jared M Brown
- School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Holger K Eltzschig
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Elizabeth A Jacobsen
- Division of Allergy, Asthma and Clinical Immunology, Mayo Clinic Arizona, Scottsdale, AZ 85259, USA
| | - Cynthia Ju
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
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30
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Abstract
Mucosal surfaces are distinctive sites exposed to environmental, dietary, and microbial antigens. Particularly in the gut, the host continuously actively adapts via complex interactions between the microbiota and dietary compounds and immune and other tissue cells. Regulatory T cells (Tregs) are critical for tuning the intestinal immune response to self- and non-self-antigens in the intestine. Its importance in intestinal homeostasis is illustrated by the onset of overt inflammation caused by deficiency in Treg generation, function, or stability in the gut. A substantial imbalance in Tregs has been observed in intestinal tissue during pathogenic conditions, when a tightly regulated and equilibrated system becomes dysregulated and leads to unimpeded and chronic immune responses. In this chapter, we compile and critically discuss the current knowledge on the key factors that promote Treg-mediated tolerance in the gut, such as those involved in intestinal Treg differentiation, specificity and suppressive function, and their immunophenotype during health and disease. We also discuss the current state of knowledge on Treg dysregulation in human intestine during pathological states such as inflammatory bowel disease (IBD), necrotizing enterocolitis (NEC), graft-versus-host disease (GVHD), and colorectal cancer (CRC), and how that knowledge is guiding development of Treg-targeted therapies to treat or prevent intestinal disorders.
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31
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Huang Q, Ma X, Wang Y, Niu Z, Wang R, Yang F, Wu M, Liang G, Rong P, Wang H, Harris DC, Wang W, Cao Q. IL-10 producing type 2 innate lymphoid cells prolong islet allograft survival. EMBO Mol Med 2020; 12:e12305. [PMID: 33034128 PMCID: PMC7645373 DOI: 10.15252/emmm.202012305] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 09/15/2020] [Accepted: 09/16/2020] [Indexed: 12/19/2022] Open
Abstract
Type 2 innate lymphoid cells (ILC2s) are a subset of ILCs with critical roles in immunoregulation. However, the possible role of ILC2s as immunotherapy against allograft rejection remains unclear. Here, we show that IL‐33 significantly prolonged islet allograft survival. IL‐33‐treated mice had elevated numbers of ILC2s and regulatory T cells (Tregs). Depletion of Tregs partially abolished the protective effect of IL‐33 on allograft survival, and additional ILC2 depletion in Treg‐depleted DEREG mice completely abolished the protective effects of IL‐33, indicating that ILC2s play critical roles in IL‐33‐mediated islet graft protection. Two subsets of ILC2s were identified in islet allografts of IL‐33‐treated mice: IL‐10 producing ILC2s (ILC210) and non‐IL‐10 producing ILC2s (non‐ILC10). Intravenous transfer of ILC210 cells, but not non‐ILC10, prolonged islet allograft survival in an IL‐10‐dependent manner. Locally transferred ILC210 cells led to long‐term islet graft survival, suggesting that ILC210 cells are required within the allograft for maximal suppressive effect and graft protection. This study has uncovered a major protective role of ILC210 in islet transplantation which could be potentiated as a therapeutic strategy.
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Affiliation(s)
- Qingsong Huang
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
| | - Xiaoqian Ma
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia.,The Institute for Cell Transplantation and Gene Therapy, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Yiping Wang
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia
| | - Zhiguo Niu
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
| | - Ruifeng Wang
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia
| | - Fuyan Yang
- The Department of Nephrology, First People's Hospital of Xinxiang Medical University, Xinxiang, China
| | - Menglin Wu
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
| | - Guining Liang
- The Department of Physiology, Guangxi Medical University, Nanning, China
| | - Pengfei Rong
- The Institute for Cell Transplantation and Gene Therapy, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Hui Wang
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
| | - David Ch Harris
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia
| | - Wei Wang
- The Institute for Cell Transplantation and Gene Therapy, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Qi Cao
- Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China.,Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia
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Hill GR, Koyama M. Cytokines and costimulation in acute graft-versus-host disease. Blood 2020; 136:418-428. [PMID: 32526028 PMCID: PMC7378458 DOI: 10.1182/blood.2019000952] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 01/18/2020] [Indexed: 12/11/2022] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (alloSCT) is an important curative therapy for high-risk hematological malignancies, but the development of severe and/or steroid-refractory acute graft-versus-host disease (aGVHD) remains a significant limitation to optimal outcomes. New approaches to prevent and treat aGVHD remain an unmet need that can be best addressed by understanding the complex disease pathophysiology. It is now clear that chemoradiotherapy used prior to alloSCT induces the release of endogenous alarmins (eg, HMGB-1, ATP, IL-1α, IL-33) from recipient tissue. Exogenous pathogen-derived molecules (eg, lipopolysaccharide, nucleic acids) also translocate from the gastrointestinal tract lumen. Together, these danger signals activate antigen-presenting cells (APCs) to efficiently present alloantigen to donor T cells while releasing cytokines (eg, interleukin-12 [IL-12], IL-23, IL-6, IL-27, IL-10, transforming growth factor-β) that expand and differentiate both pathogenic and regulatory donor T cells. Concurrent costimulatory signals at the APC-T-cell interface (eg, CD80/CD86-CD28, CD40-CD40L, OX40L-OX40, CD155/CD112-DNAM-1) and subsequent coinhibitory signals (eg, CD80/CD86-CTLA4, PDL1/2-PD1, CD155/CD112-TIGIT) are critical to the acquisition of effector T-cell function and ensuing secretion of pathogenic cytokines (eg, IL-17, interferon-γ, tissue necrosis factor, granulocyte-macrophage colony-stimulating factor) and cytolytic degranulation pathway effectors (eg, perforin/granzyme). This review focuses on the combination of cytokine and costimulatory networks at the T-cell surface that culminates in effector function and subsequent aGVHD in target tissue. Together, these pathways now represent robust and clinically tractable targets for preventing the initiation of deleterious immunity after alloSCT.
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Affiliation(s)
- Geoffrey R Hill
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and
- Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA
| | - Motoko Koyama
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and
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Eissmann MF, Buchert M, Ernst M. IL33 and Mast Cells-The Key Regulators of Immune Responses in Gastrointestinal Cancers? Front Immunol 2020; 11:1389. [PMID: 32719677 PMCID: PMC7350537 DOI: 10.3389/fimmu.2020.01389] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Accepted: 05/29/2020] [Indexed: 12/13/2022] Open
Abstract
The Interleukin (IL-)1 family IL33 is best known for eliciting type 2 immune responses by stimulating mast cells (MCs), regulatory T-cells (Tregs), innate lymphoid cells (ILCs) and other immune cells. MCs and IL33 provide critical control of immunological and epithelial homeostasis in the gastrointestinal (GI) tract. Meanwhile, the role of MCs in solid malignancies appears tissue-specific with both pro and anti-tumorigenic activities. Likewise, IL33 signaling significantly shapes immune responses in the tumor microenvironment, but these effects remain often dichotomous when assessed in experimental models of cancer. Thus, the balance between tumor suppressing and tumor promoting activities of IL33 are highly context dependent, and most likely dictated by the mixture of cell types responding to IL33. Adding to this complexity is the promiscuous nature by which MCs respond to cytokines other than IL33 and release chemotactic factors that recruit immune cells into the tumor microenvironment. In this review, we integrate the outcomes of recent studies on the role of MCs and IL33 in cancer with our own observations in the GI tract. We propose a working model where the most abundant IL33 responsive immune cell type is likely to dictate an overall tumor-supporting or tumor suppressing outcome in vivo. We discuss how these opposing responses affect the therapeutic potential of targeting MC and IL33, and highlight the caveats and challenges facing our ability to effectively harness MCs and IL33 biology for anti-cancer immunotherapy.
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Affiliation(s)
- Moritz F Eissmann
- Olivia Newton-John Cancer Research Institute, and La Trobe University School of Cancer Medicine, Heidelberg, VIC, Australia
| | - Michael Buchert
- Olivia Newton-John Cancer Research Institute, and La Trobe University School of Cancer Medicine, Heidelberg, VIC, Australia
| | - Matthias Ernst
- Olivia Newton-John Cancer Research Institute, and La Trobe University School of Cancer Medicine, Heidelberg, VIC, Australia
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Zhou Z, Yan F, Liu O. Interleukin (IL)-33: an orchestrator of immunity from host defence to tissue homeostasis. Clin Transl Immunology 2020; 9:e1146. [PMID: 32566227 PMCID: PMC7299676 DOI: 10.1002/cti2.1146] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Revised: 05/24/2020] [Accepted: 05/28/2020] [Indexed: 02/06/2023] Open
Abstract
Interleukin (IL)-33, a member of the IL-1 superfamily, functions as an alarm signal, which is released upon cell injury or tissue damage to alert the immune system. It has emerged as a chief orchestrator in immunity and has a broad pleiotropic action that influences differentiation, maintenance and function of various immune cell types via the ST2 receptor. Although it has been strongly associated with immunopathology, critically, IL-33 is involved in host defence, tissue repair and homeostasis. In this review, we provide an overview of the signalling pathway of IL-33 and highlight its regulatory functions in immune cells. Furthermore, we attempt a broader discussion of the emerging functions of IL-33 in host defence, tissue repair, metabolism, inflammatory disease and cancer, suggesting potential avenues to manoeuvre IL-33/ST2 signalling as treatment options.
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Affiliation(s)
- Zekun Zhou
- Hunan Key Laboratory of Oral Health Research & Hunan 3D Printing Engineering Research Center of Oral Care & Hunan Clinical Research Center of Oral Major Diseases and Oral Health & Xiangya Stomatological Hospital & Xiangya School of Stomatology Central South University Changsha Hunan China
| | - Fei Yan
- Hunan Key Laboratory of Oral Health Research & Hunan 3D Printing Engineering Research Center of Oral Care & Hunan Clinical Research Center of Oral Major Diseases and Oral Health & Xiangya Stomatological Hospital & Xiangya School of Stomatology Central South University Changsha Hunan China
| | - Ousheng Liu
- Hunan Key Laboratory of Oral Health Research & Hunan 3D Printing Engineering Research Center of Oral Care & Hunan Clinical Research Center of Oral Major Diseases and Oral Health & Xiangya Stomatological Hospital & Xiangya School of Stomatology Central South University Changsha Hunan China
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Hong YQ, Wan B, Li XF. Macrophage regulation of graft- vs-host disease. World J Clin Cases 2020; 8:1793-1805. [PMID: 32518770 PMCID: PMC7262718 DOI: 10.12998/wjcc.v8.i10.1793] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 04/08/2020] [Accepted: 04/21/2020] [Indexed: 02/05/2023] Open
Abstract
Hematopoietic stem cell transplantation has become a curative choice of many hematopoietic malignancy, but graft-vs-host disease (GVHD) has limited the survival quality and overall survival of hematopoietic stem cell transplantation. Understanding of the immune cells’ reaction in pathophysiology of GVHD has improved, but a review on the role of macrophages in GVHD is still absent. Studies have observed that macrophage infiltration is associated with GVHD occurrence and development. In this review, we summarize and analyze the role of macrophages in GVHD based on pathophysiology of acute and chronic GVHD, focusing on the macrophage recruitment and infiltration, macrophage polarization, macrophage secretion, and especially interaction of macrophages with other immune cells. We could conclude that macrophage recruitment and infiltration contribute to both acute and chronic GVHD. Based on distinguishing pathology of acute and chronic GVHD, macrophages tend to show a higher M1/M2 ratio in acute GVHD and a lower M1/M2 ratio in chronic GVHD. However, the influence of dominant cytokines in GVHD is controversial and inconsistent with macrophage polarization. In addition, interaction of macrophages with alloreactive T cells plays an important role in acute GVHD. Meanwhile, the interaction among macrophages, B cells, fibroblasts, and CD4+ T cells participates in chronic GVHD development.
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Affiliation(s)
- Ya-Qun Hong
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Department of Hematology, Fujian Medical University Union Hospital, Fuzhou 350000, Fujian Province, China
| | - Bo Wan
- Faculty of Life Sciences and Medicine, King’s College London, London WC1N 3BG, United Kingdom
| | - Xiao-Fan Li
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Department of Hematology, Fujian Medical University Union Hospital, Fuzhou 350000, Fujian Province, China
- INSERM U1160, Hospital Saint Louis, Université Paris Diderot, Paris 94430, France
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Rao UK, Engelhardt BG. Predicting Immuno-Metabolic Complications After Allogeneic Hematopoietic Cell Transplant with the Cytokine Interleukin-33 (IL-33) and its Receptor Serum-Stimulation 2 (ST2). Clin Hematol Int 2020; 2:101-108. [PMID: 34595450 PMCID: PMC8432328 DOI: 10.2991/chi.d.200506.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 05/04/2020] [Indexed: 01/19/2023] Open
Abstract
Patients undergoing allogeneic hematopoietic cell transplantation (HCT) are at risk for numerous acute and long-term complications from this procedure. Post-transplant diabetes mellitus (PTDM) is a common but under-recognized problem. Similar to graft-versus-host disease (GVHD), new-onset diabetes is characterized by immune dysregulation that can negatively impact transplant outcomes. This review will discuss the biology of IL-33/ST2 in acute GVHD and PTDM development, and how this cytokine axis could be leveraged for predicting and treating immuno-metabolic complications after transplant.
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Affiliation(s)
- Uttam K Rao
- Department of Medicine, Vanderbilt University Medical Center, Medical Center Drive, Nashville, TN, USA
| | - Brian G Engelhardt
- Department of Medicine, Vanderbilt University Medical Center, Medical Center Drive, Nashville, TN, USA
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The Role of IL-33 in Experimental Heart Transplantation. Cardiol Res Pract 2020; 2020:6108362. [PMID: 32257426 PMCID: PMC7106886 DOI: 10.1155/2020/6108362] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 11/24/2019] [Accepted: 12/31/2019] [Indexed: 01/17/2023] Open
Abstract
Interleukin-33 (IL-33) is a member of the IL-1 family of proteins that are produced by a variety of cell types in multiple tissues. Under conditions of cell injury or death, IL-33 is passively released from the nucleus and acts as an "alarmin" upon binding to its specific receptor ST2, which leads to proinflammatory or anti-inflammatory effects depending on the pathological environment. To date, numerous studies have investigated the roles of IL-33 in human and murine models of diseases of the nervous system, digestive system, pulmonary system, as well as other organs and systems, including solid organ transplantation. With graft rejection and ischemia-reperfusion injury being the most common causes of grafted organ failure or dysfunction, researchers have begun to investigate the role of IL-33 in the immune-related mechanisms of graft tolerance and rejection using heart transplantation models. In the present review, we summarize the identified roles of IL-33 as well as the corresponding mechanisms by which IL-33 acts within the progression of graft rejection after heart transplantation in animal models.
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Bcl6 and Blimp1 reciprocally regulate ST2 + Treg-cell development in the context of allergic airway inflammation. J Allergy Clin Immunol 2020; 146:1121-1136.e9. [PMID: 32179158 DOI: 10.1016/j.jaci.2020.03.002] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 02/12/2020] [Accepted: 03/03/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Bcl6 is required for the development of T follicular helper cells and T follicular regulatory (Tfr) cells that regulate germinal center responses. Bcl6 also affects the function of regulatory T (Treg) cells. OBJECTIVE The goal of this study was to define the functions of Bcl6 in Treg cells, including Tfr cells, in the context of allergic airway inflammation. METHODS We used a model of house dust mite sensitization to challenge wild-type, Bcl6fl/fl Foxp3-Cre, and Prdm1 (Blimp1)fl/fl Foxp3-Cre mice to study the reciprocal roles of Bcl6 and Blimp1 in allergic airway inflammation. RESULTS In the house dust mite model, Tfr cells repress the production of IgE and Bcl6+ Treg cells suppress the generation of type 2 cytokine-producing cells in the lungs. In mice with Bcl6-deficient Treg cells, twice as many ST2+ (IL-33R+) Treg cells develop as are observed in wild-type mice. ST2+ Treg cells in the context of allergic airway inflammation are Blimp1 dependent, express type 2 cytokines, and share features of visceral adipose tissue Treg cells. Bcl6-deficient Treg cells are more susceptible, and Blimp1-deficient Treg cells are resistant, to acquiring the ST2+ Treg-cell phenotype in vitro and in vivo in response to IL-33. Bcl6-deficient ST2+ Treg cells, but not Bcl6-deficient ST2+ conventional T cells, strongly promote allergic airway inflammation when transferred into recipient mice. Lastly, ST2 is required for the exacerbated allergic airway inflammation in Bcl6fl/fl Foxp3-Cre mice. CONCLUSIONS During allergic airway inflammation, Bcl6 and Blimp1 play dual roles in regulating Tfr-cell activity in the germinal center and in the development of ST2+ Treg cells that promote type 2 cytokine responses.
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Matsumura A, Miyazaki T, Tachibana T, Ando T, Koyama M, Koyama S, Ishii Y, Takahashi H, Nakajima Y, Numata A, Yamamoto W, Motohashi K, Hagihara M, Matsumoto K, Fujisawa S, Nakajima H. Predictive Values of Early Suppression of Tumorigenicity 2 for Acute GVHD and Transplant-related Complications after Allogeneic Stem Cell Transplantation: Prospective Observational Study. Turk J Haematol 2020; 37:20-29. [PMID: 31464120 PMCID: PMC7057758 DOI: 10.4274/tjh.galenos.2019.2019.0139] [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: 04/02/2019] [Accepted: 08/28/2019] [Indexed: 12/04/2022] Open
Abstract
Objective A soluble form of suppression of tumorigenicity 2 (sST2) has emerged as a biomarker for acute graft-versus-host disease (GVHD) and non-relapse mortality (NRM). We prospectively monitored sST2 levels during the early phase of hematopoietic stem cell transplantation (HSCT) and evaluated the clinical association with transplant-related complications including acute GVHD. Materials and Methods Thirty-two adult Japanese patients who received a first allogeneic HSCT were enrolled in this study. Levels of sST2 were measured at fixed time points (pre-conditioning, day 0, day 14, day 21, and day 28). Results The median age was 50.5 years (range=16-66). With a median follow-up of 21.5 months (range=0.9-35.4), 9 patients developed grade II-IV acute GVHD. Median sST2 levels on the day of HSCT were higher than baseline and reached the maximum value (92.7 ng/mL; range=0-419.7) on day 21 after HSCT. The optimal cut-off value of sST2 on day 14 for predicting grade II-IV acute GVHD was determined as 100 ng/mL by ROC analysis. The cumulative incidence of acute GVHD was 56.7% and 16.5% in the high- and low-sST2 groups, respectively (p<0.01). Multivariate analyses showed that high sST2 levels at day 14 were associated with a higher incidence of acute GVHD (hazard ratio=9.35, 95% confidence interval=2.92-30.0, p<0.01). The cumulative incidence of NRM was increased in the highs-ST2 group (33% vs 0%, p<0.01), but all the patients died of non-GVHD complications. Among 6 patients in the high-sST2 group without grade II-IV GVHD, 5 patients developed veno-occlusive disease (VOD) and one also had thrombotic microangiopathy (TMA). Conclusion The early assessment of sST2 after HSCT yielded predictive values for the onset of acute GVHD and other transplant-related complications including VOD and TMA.
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Affiliation(s)
- Ayako Matsumura
- Yokohama City University Graduate School of Medicine, Department of Stem Cell and Immune Regulation, Kanagawa, Japan
| | - Takuya Miyazaki
- Yokohama City University Graduate School of Medicine, Department of Stem Cell and Immune Regulation, Kanagawa, Japan
| | - Takayoshi Tachibana
- Yokohama City University Graduate School of Medicine, Department of Stem Cell and Immune Regulation, Kanagawa, Japan
| | - Taiki Ando
- Yokohama City University Medical Center, Department of Hematology, Kanagawa, Japan
| | - Megumi Koyama
- Yokohama City University Medical Center, Department of Hematology, Kanagawa, Japan
| | - Satoshi Koyama
- Yokohama City University Medical Center, Department of Hematology, Kanagawa, Japan
| | - Yoshimi Ishii
- Yokohama City University Medical Center, Department of Hematology, Kanagawa, Japan
| | - Hiroyuki Takahashi
- Yokohama City University Graduate School of Medicine, Department of Stem Cell and Immune Regulation, Kanagawa, Japan
| | - Yuki Nakajima
- Yokohama City University Graduate School of Medicine, Department of Stem Cell and Immune Regulation, Kanagawa, Japan
| | - Ayumi Numata
- Yokohama City University Medical Center, Department of Hematology, Kanagawa, Japan
| | - Wataru Yamamoto
- Yokohama City University Medical Center, Department of Hematology, Kanagawa, Japan
| | - Kenji Motohashi
- Yokohama City University Medical Center, Department of Hematology, Kanagawa, Japan
| | - Maki Hagihara
- Yokohama City University Graduate School of Medicine, Department of Stem Cell and Immune Regulation, Kanagawa, Japan
| | - Kenji Matsumoto
- Yokohama City University Graduate School of Medicine, Department of Stem Cell and Immune Regulation, Kanagawa, Japan
| | - Shin Fujisawa
- Yokohama City University Medical Center, Department of Hematology, Kanagawa, Japan
| | - Hideaki Nakajima
- Yokohama City University Graduate School of Medicine, Department of Stem Cell and Immune Regulation, Kanagawa, Japan
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Chen Z, Bozec A, Ramming A, Schett G. Anti-inflammatory and immune-regulatory cytokines in rheumatoid arthritis. Nat Rev Rheumatol 2020; 15:9-17. [PMID: 30341437 DOI: 10.1038/s41584-018-0109-2] [Citation(s) in RCA: 432] [Impact Index Per Article: 86.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by a failure of spontaneous resolution of inflammation. Although the pro-inflammatory cytokines and mediators that trigger RA have been the focus of intense investigations, the regulatory and anti-inflammatory cytokines responsible for the suppression and resolution of disease in a context-dependent manner have been less well characterized. However, knowledge of the pathways that control the suppression and resolution of inflammation in RA is clinically relevant and conceptually important for understanding the pathophysiology of the disease and for the development of treatments that enable long-term remission. Cytokine-mediated processes such as the activation of T helper 2 cells by IL-4 and IL-13, the resolution of inflammation by IL-9, IL-5-induced eosinophil expansion, IL-33-mediated macrophage polarization, the production of IL-10 by regulatory B cells and IL-27-mediated suppression of lymphoid follicle formation are all involved in governing the regulation and resolution of inflammation in RA. By better understanding these immune-regulatory signalling pathways, new therapeutic strategies for RA can be envisioned that aim to balance and resolve, rather than suppress, inflammation.
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Affiliation(s)
- Zhu Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of the University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Aline Bozec
- Department of Internal Medicine 3, Friedrich Alexander University Erlangen-Nuremberg and Universitatsklinikum Erlangen, Erlangen, Germany
| | - Andreas Ramming
- Department of Internal Medicine 3, Friedrich Alexander University Erlangen-Nuremberg and Universitatsklinikum Erlangen, Erlangen, Germany
| | - Georg Schett
- Department of Internal Medicine 3, Friedrich Alexander University Erlangen-Nuremberg and Universitatsklinikum Erlangen, Erlangen, Germany.
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Smith BM, Lyle MJ, Chen AC, Miao CH. Antigen-specific in vitro expansion of factor VIII-specific regulatory T cells induces tolerance in hemophilia A mice. J Thromb Haemost 2020; 18:328-340. [PMID: 31609041 PMCID: PMC6994379 DOI: 10.1111/jth.14659] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 09/25/2019] [Accepted: 10/07/2019] [Indexed: 12/27/2022]
Abstract
BACKGROUND Following protein replacement therapy, one-third of severe hemophilia A patients develop antibodies to factor VIII (FVIII), which also hinders the efficacy of gene therapy. Regulatory T cells (Tregs) have a naturally suppressive function that potentially reduces the immune response to FVIII therapy. Furthermore, antigen-specific Tregs are functionally much more potent than polyclonal cells. Adoptive transfer of antigen-specific Tregs can effectively suppress anti-FVIII antibody responses. OBJECTIVE Develop a clinically feasible protocol to enrich and expand Tregs specific to FVIII for suppressing anti-FVIII immune responses. METHODS Regulatory T cells are isolated from FVIII-sensitized mice, sorted on CD25high markers, and expanded specifically with FVIII, antigen-presenting cells, and interleukin 2 (IL 2). Subsequently, Tregs are further cultured with anti-CD3/anti-CD28 beads, anti-Crry antibodies, and IL 2 to achieve 10-fold to 20-fold expansion. Expanded Tregs are characterized and tested for their suppressive activity in vitro and in vivo. RESULTS In vitro FVIII-specific suppressive assays indicate that FVIII specifically expanded Tregs are more suppressive than non-specifically expanded and naive Tregs. Adoptive transfer of expanded Tregs into HemA mice showed that FVIII-specifically expanded Tregs are significantly more potent in suppressing anti-FVIII immune responses in FVIII plasmid-treated HemA mice. Moreover, the FVIII-specific immune tolerance is maintained after a secondary challenge with FVIII plasmid. CONCLUSIONS Our results demonstrate that the FVIII-specific sensitization and expansion protocol yields more potent Tregs to suppress anti-FVIII antibody responses and induce long-term tolerance to FVIII, increasing the potential for adoptive Treg cell therapy to modulate anti-FVIII immune responses.
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Affiliation(s)
- Bryn M Smith
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington
| | - Meghan J Lyle
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington
| | - Alex C Chen
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington
| | - Carol H Miao
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington
- Department of Pediatrics, University of Washington, Seattle, Washington
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Hasan A, Kochumon S, Al-Ozairi E, Tuomilehto J, Al-Mulla F, Ahmad R. Correlation Profile of Suppression of Tumorigenicity 2 and/or Interleukin-33 with Biomarkers in the Adipose Tissue of Individuals with Different Metabolic States. Diabetes Metab Syndr Obes 2020; 13:3839-3859. [PMID: 33116731 PMCID: PMC7586022 DOI: 10.2147/dmso.s251978] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Accepted: 08/01/2020] [Indexed: 12/14/2022] Open
Abstract
PURPOSE The suppression of tumorigenicity 2 (ST2) has two main splice variants including a membrane bound (ST2) form, which activates the myeloid differentiation primary response 88 (MyD88)/nuclear factor-kappa B (NF-κB) signaling pathway, and a secreted soluble form (sST2), which acts as a decoy receptor for ST2 ligand, interleukin (IL)-33. The IL-33/ST2 axis is protective against obesity, insulin resistance, and type 2 diabetes (T2D). In humans, adipose tissue IL-33 displays distinct correlation profiles with glycated hemoglobin, ST2, and other immunometabolic mediators, depending on the glycemic health of the individuals. We determined whether adipose tissue ST2 displays distinct correlation profiles with immunometabolic mediators and whether ST2 and/or IL-33 are correlated with intracellular signaling molecules. PATIENTS AND METHODS A total of 91 adults with normal glycemia, prediabetes, and T2D were included. After measuring their anthropometric and biochemical parameters, subcutaneous adipose tissues were isolated and mRNA expression of biomarkers was measured. RESULTS In individuals with normal glycemia, adipose tissue ST2 was directly correlated with chemokine (C-C motif) ligand (CCL)-2, CCL5, IL-12, fibrinogen-like protein 2 (FGL2) and interferon regulatory factor (IRF)-4, but inversely correlated with cytochrome C oxidase subunit 7A1. IL-33 and ST2 were directly correlated with tumor necrosis factor receptor-associated factor 6 (TRAF6), NF-κB, and nuclear factor of activated T-cells 5 (NFAT5). In individuals with prediabetes, ST2 was inversely correlated with IL-5, whereas IL-33 but not ST2 was directly correlated with MyD88 and NF-κB. In individuals with T2D, ST2 was directly correlated with CCL2, IL-1β, and IRF5. IL-33 and ST2 were directly correlated with MyD88, TRAF6, and NF-κB. CONCLUSION Adipose tissue ST2 and IL-33 show different correlation profiles with various immunometabolic biomarkers depending on the metabolic state of the individuals. Therefore, targeting the IL-33/ST2 axis might form the basis for novel therapies to combat metabolic disorders.
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Affiliation(s)
- Amal Hasan
- Department of Immunology and Microbiology, Dasman Diabetes Institute, Kuwait City, Kuwait
- Correspondence: Amal Hasan Email
| | - Shihab Kochumon
- Department of Immunology and Microbiology, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Ebaa Al-Ozairi
- Clinical Research Unit, Medical Division, Dasman Diabetes Institute, Kuwait City, Kuwait
- Department of Medicine, Faculty of Medicine, Kuwait City, Kuwait
| | - Jaakko Tuomilehto
- Research Division, Dasman Diabetes Institute, Kuwait City, Kuwait
- Department of Public Health, University of Helsinki, Helsinki, Finland
- National School of Public Health, Madrid, Spain
| | - Fahd Al-Mulla
- Department of Genetics and Bioinformatics, Functional Genomics, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Rasheed Ahmad
- Department of Immunology and Microbiology, Dasman Diabetes Institute, Kuwait City, Kuwait
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Wang R, Feng W, Wang H, Wang L, Yang X, Yang F, Zhang Y, Liu X, Zhang D, Ren Q, Feng X, Zheng G. Blocking migration of regulatory T cells to leukemic hematopoietic microenvironment delays disease progression in mouse leukemia model. Cancer Lett 2019; 469:151-161. [PMID: 31669202 DOI: 10.1016/j.canlet.2019.10.032] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 10/11/2019] [Accepted: 10/21/2019] [Indexed: 02/06/2023]
Abstract
Blocking the migration of regulatory T cells (Tregs) to the tumor microenvironment is a promising strategy for tumor immunotherapy. Treg accumulation in the leukemic hematopoietic microenvironment (LHME) has adverse impacts on patient outcomes. The mechanism and effective methods of disrupting Treg accumulation in the LHME have not been well established. Here, we studied the distribution and characteristics of Tregs in the LHME, investigated the effects of Treg ablation on leukemia progression, explored the mechanisms leading to Treg accumulation, and studied whether blocking Treg migration to the LHME delayed leukemia progression in MLL-AF9-induced mouse acute myeloid leukemia (AML) models using wildtype (WT) and Foxp3DTR/GFP mice. Increased accumulation of more activated Tregs was detected in the LHME. Inducible Treg ablation prolonged the survival of AML mice by promoting the antileukemic effects of CD8+ T cells. Furthermore, both local expansion and migration accounted for Treg accumulation in the LHME. Moreover, blocking the CCL3-CCR1/CCR5 and CXCL12-CXCR4 axes inhibited Treg accumulation in the LHME and delayed leukemia progression. Our findings provide laboratory evidence for a potential leukemia immunotherapy by blocking the migration of Tregs.
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Affiliation(s)
- Rong Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Wenli Feng
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Hao Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Lina Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Xiao Yang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Feifei Yang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Yingchi Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Xiaoli Liu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Dongyue Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Qian Ren
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Xiaoming Feng
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China
| | - Guoguang Zheng
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China.
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Elevations in Circulating sST2 Levels Are Associated With In-Hospital Mortality and Adverse Clinical Outcomes After Blunt Trauma. J Surg Res 2019; 244:23-33. [PMID: 31279260 DOI: 10.1016/j.jss.2019.05.057] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 04/09/2019] [Accepted: 05/30/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND Soluble suppression of tumorigenicity 2 (sST2), a decoy receptor for interleukin (IL)-33, has emerged as a novel biomarker in various disease processes. Recent studies have elucidated the role of the sST2/IL-33 complex in modulating the balance of Th1/Th2 immune responses after tissue stress. However, the role of sST2 as a biomarker after traumatic injury remains unclear. To address this, we evaluated serum sST2 correlations with mortality and in-hospital adverse outcomes as endpoints in blunt trauma patients. METHODS We retrospectively analyzed clinical and biobank data of 493 blunt trauma victims 472 survivors (mean age: 48.4 ± 0.87; injury severity score [ISS]: 19.6 ± 0.48) and 19 nonsurvivors (mean age: 58.8 ± 4.5; ISS: 23.3 ± 2.1) admitted to the intensive care unit. Given the confounding impact of age on the inflammatory response, we derived a propensity-matched survivor subgroup (n = 19; mean age: 59 ± 3; ISS: 23.4 ± 2) using an IBM SPSS case-control matching algorithm. Serial blood samples were obtained from all patients (3 samples within the first 24 h and then once daily from day [D] 1 to D5 after injury). sST2 and twenty-nine inflammatory biomarkers were assayed using enzyme-linked immunosorbent assay and Luminex, respectively. Two-way analysis of variance on ranks was used to compare groups (P < 0.05). Spearman rank correlation was performed to determine the association of circulating sST2 levels with biomarker levels and in-hospital clinical outcomes. RESULTS Circulating sST2 levels of the nonsurvivor cohort were statistically significantly elevated at 12 h after injury and remained elevated up to D5 when compared either to the overall 472 survivor cohort or a matched 19 survivor subcohort. Admission sST2 levels obtained from the first blood draw after injury in the survivor cohort correlated positively with admission base deficit (correlation coefficient [CC] = 0.1; P = 0.02), international normalized ratio (CC = 0.1, P = 0.03), ISS (CC = 0.1, P = 0.008), and the average Marshall multiple organ dysfunction score between D2 and D5 (CC = 0.1, P = 0.04). Correlations with ISS revealed a positive correlation of ISS with plasma sST2 levels across the mild ISS (CC = 0.47, P < 0.001), moderate ISS (CC = 0.58, P < 0.001), and severe ISS groups (CC = 0.63, P < 0.001). Analysis of biomarker correlations in the matched survivor group over the initial 24 h after injury showed that sST2 correlates strongly and positively with IL-4 (CC = 0.65, P = 0.002), IL-5 (CC = 0.57, P = 0.01), IL-21 (CC = 0.52, P = 0.02), IL-2 (CC = 0.51, P = 0.02), soluble IL-2 receptor-α (CC = 0.5, P = 0.02), IL-13 (CC = 0.49, P = 0.02), and IL-17A (CC = 0.48, P = 0.03). This was not seen in the matched nonsurvivor group. sST2/IL-33 ratios were significantly elevated in nonsurvivors and patients with severe injury based on ISS ≥ 25. CONCLUSIONS Elevations in serum sST2 levels are associated with poor clinical trajectories and mortality after blunt trauma. High sST2 coupled with low IL-33 associates with severe injury, mortality, and worse clinical outcomes. These findings suggest that sST2 could serve as an early prognostic biomarker in trauma patients and that sustained elevations of sST2 could contribute to a detrimental suppression of IL-33 bioavailability in patients with high injury severity.
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Copsel S, Wolf D, Komanduri KV, Levy RB. The promise of CD4 +FoxP3 + regulatory T-cell manipulation in vivo: applications for allogeneic hematopoietic stem cell transplantation. Haematologica 2019; 104:1309-1321. [PMID: 31221786 PMCID: PMC6601084 DOI: 10.3324/haematol.2018.198838] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 05/07/2019] [Indexed: 12/12/2022] Open
Abstract
CD4+FoxP3+ regulatory T cells (Tregs) are a non-redundant population critical for the maintenance of self-tolerance. Over the past decade, the use of these cells for therapeutic purposes in transplantation and autoimmune disease has emerged based on their capacity to inhibit immune activation. Basic science discoveries have led to identifying key receptors on Tregs that can regulate their proliferation and function. Notably, the understanding that IL-2 signaling is crucial for Treg homeostasis promoted the hypothesis that in vivo IL-2 treatment could provide a strategy to control the compartment. The use of low-dose IL-2 in vivo was shown to selectively expand Tregs versus other immune cells. Interestingly, a number of other Treg cell surface proteins, including CD28, CD45, IL-33R and TNFRSF members, have been identified which can also induce activation and proliferation of this population. Pre-clinical studies have exploited these observations to prevent and treat mice developing autoimmune diseases and graft-versus-host disease post-allogeneic hematopoietic stem cell transplantation. These findings support the development of translational strategies to expand Tregs in patients. Excitingly, the use of low-dose IL-2 for patients suffering from graft-versus-host disease and autoimmune disease has demonstrated increased Treg levels together with beneficial outcomes. To date, promising pre-clinical and clinical studies have directly targeted Tregs and clearly established the ability to increase their levels and augment their function in vivo. Here we review the evolving field of in vivo Treg manipulation and its application to allogeneic hematopoietic stem cell transplantation.
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Affiliation(s)
| | | | - Krishna V Komanduri
- Department of Microbiology and Immunology.,Sylvester Comprehensive Cancer Center.,Division of Transplantation and Cellular Therapy, Department of Medicine
| | - Robert B Levy
- Department of Microbiology and Immunology .,Division of Transplantation and Cellular Therapy, Department of Medicine.,Department of Ophthalmology, Miller School of Medicine, University of Miami, FL, USA
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IL233, an IL-2-IL-33 hybrid cytokine induces prolonged remission of mouse lupus nephritis by targeting Treg cells as a single therapeutic agent. J Autoimmun 2019; 102:133-141. [PMID: 31103267 DOI: 10.1016/j.jaut.2019.05.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 05/01/2019] [Accepted: 05/04/2019] [Indexed: 12/29/2022]
Abstract
Lupus glomerulonephritis (GN) is an autoimmune disease characterized by immune complex-deposition, complement activation and glomerular inflammation. In lupus-prone NZM2328 mice, the occurrence of lupus GN was accompanied by a decrease in Treg cells and an increase in proinflammatory cytokine-producing T cells. Because IL-33 in addition to IL-2 has been shown to be important for Treg cell proliferation and ST2 (IL-33 receptor) positive Treg cells are more potent in suppressor activity, a hybrid cytokine with active domains of IL-2 and IL-33 was generated to target the ST2+ Treg cells as a therapeutic agent to treat lupus GN. Three mouse models were used: spontaneous and Ad-IFNα- accelerated lupus GN in NZM2328 and the lymphoproliferative autoimmune GN in MRL/lpr mice. Daily injections of IL233 for 5 days prevented Ad-IFNα-induced lupus GN and induced remission of spontaneous lupus GN. The remission was permanent in that no relapses were detected. The remission was accompanied by persistent elevation of Treg cells in the renal lymph nodes. IL233 is more potent than IL-2 and IL-33 either singly or in combination in the treatment of lupus GN. The results of this study support the thesis that IL233 should be considered as a novel agent for treating lupus GN.
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Matsuoka S, Hashimoto D, Kadowaki M, Ohigashi H, Hayase E, Yokoyama E, Hasegawa Y, Tateno T, Chen X, Aoyama K, Oka H, Onozawa M, Takeda K, Akashi K, Teshima T. Myeloid differentiation factor 88 signaling in donor T cells accelerates graft- versus-host disease. Haematologica 2019; 105:226-234. [PMID: 31048358 PMCID: PMC6939524 DOI: 10.3324/haematol.2018.203380] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 04/30/2019] [Indexed: 01/30/2023] Open
Abstract
Myeloid differentiation factor 88 (MyD88) signaling has a crucial role in activation of both innate and adoptive immunity. MyD88 transduces signals via Toll-like receptor and interleukin-1 receptor superfamily to the NFκB pathway and inflammasome by forming a molecular complex with interleukin-1 receptor-associated kinase 4. The MyD88/interleukin-1 receptor-associated kinase 4 pathway plays an important role, not only in innate immunity, but also T-cell immunity; however, its role in donor T cells on the pathophysiology of graft-versus-host disease (GvHD) remains to be elucidated. We addressed this issue by using MyD88-deficient T cells in a mouse model of allogeneic hematopoietic stem cell transplantation (allo-SCT). While MyD88-deficient and wild-type T cells proliferated equivalently after transplantation, MyD88-deficient T cells demonstrated impaired survival and differentiation toward Th1, Tc1, and Th17, and induced less severe GvHD compared to wild-type T cells. Administration of interleukin-1 receptor-associated kinase 4 inhibitor PF-06650833 significantly ameliorated GvHD after allo-SCT. These results thus demonstrate that donor T-cell MyD88/interleukin-1 receptor-associated kinase 4 pathway is a novel therapeutic target against GvHD after allo-SCT.
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Affiliation(s)
- Satomi Matsuoka
- Department of Hematology, Faculty of Medicine, Hokkaido University, Sapporo
| | - Daigo Hashimoto
- Department of Hematology, Faculty of Medicine, Hokkaido University, Sapporo
| | - Masanori Kadowaki
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka
| | - Hiroyuki Ohigashi
- Department of Hematology, Faculty of Medicine, Hokkaido University, Sapporo
| | - Eiko Hayase
- Department of Hematology, Faculty of Medicine, Hokkaido University, Sapporo
| | - Emi Yokoyama
- Department of Hematology, Faculty of Medicine, Hokkaido University, Sapporo
| | - Yuta Hasegawa
- Department of Hematology, Faculty of Medicine, Hokkaido University, Sapporo
| | - Takahiro Tateno
- Department of Hematology, Faculty of Medicine, Hokkaido University, Sapporo
| | - Xuanzhong Chen
- Department of Hematology, Faculty of Medicine, Hokkaido University, Sapporo
| | - Kazutoshi Aoyama
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka
| | - Hideyo Oka
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka
| | - Masahiro Onozawa
- Department of Hematology, Faculty of Medicine, Hokkaido University, Sapporo
| | - Kiyoshi Takeda
- Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan
| | - Koichi Akashi
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka
| | - Takanori Teshima
- Department of Hematology, Faculty of Medicine, Hokkaido University, Sapporo
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Gabryelska A, Kuna P, Antczak A, Białasiewicz P, Panek M. IL-33 Mediated Inflammation in Chronic Respiratory Diseases-Understanding the Role of the Member of IL-1 Superfamily. Front Immunol 2019; 10:692. [PMID: 31057533 PMCID: PMC6477074 DOI: 10.3389/fimmu.2019.00692] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Accepted: 03/13/2019] [Indexed: 12/19/2022] Open
Abstract
Interleukin 33 (IL-33) is an alarmin cytokine from the IL-1 family. IL-33 is localized in the nucleus and acts there as a gene regulator. Following injury, stress or cell death, it is released from the nucleus, and exerts its pro-inflammatory biological functions via the transmembrane form of the ST2 receptor, which is present mainly as attached to immune cells. In recent years, IL-33 became a focus of many studies due to its possible role in inflammatory disorders. Among respiratory disorders, the contribution of IL-33 to the development of asthma, in particular, has been most identified. Increased level of IL-33 in lung epithelial cells and blood serum has been observed in asthma patients. The IL-33/ST2 interaction activated the Th2 mediated immune response and further production of many pro-inflammatory cytokines. Single nucleotide polymorphisms in the IL-33 gene cause a predisposition to the development of asthma. Similarly, in chronic pulmonary obstructive disease (COPD), both increased expression of IL-33 and the ST2 receptor has been observed. Interestingly, cigarette smoke, a key inducer of COPD, not only activates IL-33 production by epithelial and endothelial cells, but also induces the expression of IL-33 in peripheral blood mononuclear cells. Knowledge regarding its contribution in other respiratory disorders, such as obstructive sleep apnea, remains greatly limited. Recently it was shown that IL-33 is one of the inflammatory mediators by which levels in blood serum are increased in OSA patients, compared to healthy control patients. This mini review summarizes current knowledge on IL-33 involvement in chosen chronic respiratory disorders and proposes this interleukin as a possible link in the pathogenesis of these diseases.
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Affiliation(s)
- Agata Gabryelska
- Department of Sleep Medicine and Metabolic Disorders, Medical University of Lodz, Łódz, Poland.,Department of Internal Medicine, Asthma and Allergy, Medical University of Lodz, Łódz, Poland
| | - Piotr Kuna
- Department of Internal Medicine, Asthma and Allergy, Medical University of Lodz, Łódz, Poland
| | - Adam Antczak
- Department of General and Oncological Pulmonology, Medical University of Lodz, Łódz, Poland
| | - Piotr Białasiewicz
- Department of Sleep Medicine and Metabolic Disorders, Medical University of Lodz, Łódz, Poland
| | - Michał Panek
- Department of Internal Medicine, Asthma and Allergy, Medical University of Lodz, Łódz, Poland
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Griesenauer B, Jiang H, Yang J, Zhang J, Ramadan AM, Egbosiuba J, Campa K, Paczesny S. ST2/MyD88 Deficiency Protects Mice against Acute Graft-versus-Host Disease and Spares Regulatory T Cells. THE JOURNAL OF IMMUNOLOGY 2019; 202:3053-3064. [PMID: 30979817 DOI: 10.4049/jimmunol.1800447] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 03/18/2019] [Indexed: 12/11/2022]
Abstract
Acute graft-versus-host disease (aGVHD) hinders the efficacy of allogeneic hematopoietic cell transplantation (HCT). Plasma levels of soluble membrane-bound ST2 (ST2) are elevated in human and murine aGVHD and correlated to type 1 T cells response. ST2 signals through the adapter protein MyD88. The role of MyD88 in T cells during aGVHD has yet to be elucidated. We found that knocking out MyD88 in the donor T cells protected against aGVHD independent of IL-1R and TLR4 signaling in two murine HCT models. This protection was entirely driven by MyD88-/- CD4 T cells. Transplanting donor MyD88-/- conventional T cells (Tcons) with wild-type (WT) or MyD88-/- regulatory T cells (Tregs) lowered aGVHD severity and mortality. Transcriptome analysis of sorted MyD88-/- CD4 T cells from the intestine 10 d post-HCT showed lower levels of Il1rl1 (gene of ST2), Ifng, Csf2, Stat5, Batf, and Jak2 Transplanting donor ST2-/- Tcons with WT or ST2-/- Tregs showed a similar phenotype with what we observed when using donor MyD88-/- Tcons. Decreased ST2 was confirmed at the protein level with less secretion of soluble ST2 and more expression of ST2 compared with WT T cells. Our data suggest that Treg suppression from lack of MyD88 signaling in donor Tcons during alloreactivity uses the ST2 but not the IL-1R or TLR4 pathways, and ST2 represents a potential aGVHD therapeutic target sparing Tregs.
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Affiliation(s)
| | - Hua Jiang
- Indiana University School of Medicine, Indianapolis, IN 46202
| | - Jinfeng Yang
- Indiana University School of Medicine, Indianapolis, IN 46202
| | - Jilu Zhang
- Indiana University School of Medicine, Indianapolis, IN 46202
| | | | - Jane Egbosiuba
- Indiana University School of Medicine, Indianapolis, IN 46202
| | - Khaled Campa
- Indiana University School of Medicine, Indianapolis, IN 46202
| | - Sophie Paczesny
- Indiana University School of Medicine, Indianapolis, IN 46202
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Association between Adipose Tissue Interleukin-33 and Immunometabolic Markers in Individuals with Varying Degrees of Glycemia. DISEASE MARKERS 2019; 2019:7901062. [PMID: 31073344 PMCID: PMC6470453 DOI: 10.1155/2019/7901062] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 12/17/2018] [Indexed: 12/24/2022]
Abstract
Introduction Interleukin-33 (IL-33), the ligand for the receptor ST2, is abundant in adipose tissue, including preadipocytes, adipocytes, and endothelial cells. The IL-33/ST2 axis is protective against obesity, insulin resistance, and type 2 diabetes (T2D) in animal models. We determined whether adipose tissue IL-33 was associated with glycated hemoglobin (HbA1c), as well as mediators of inflammation and immune regulation and beiging of adipose tissue, among individuals with varying degrees of glycemia. Materials and Methods A total of 91 adults with normoglycemia, prediabetes, and T2D were included. After measuring their anthropometric and biochemical parameters, subcutaneous adipose tissue samples were isolated and mRNA expression of cytokines, chemokines, chemokine receptors, pattern recognition receptors, and mediators involved in beiging of adipose tissue were measured. Results Adipose tissue IL-33 was inversely associated with HbA1c in individuals with normoglycemia and T2D but not in those with prediabetes and was inversely correlated with fasting plasma glucose in individuals with T2D and with a better glycemic control. IL-33-to-ST2 ratio was inversely correlated with HbA1c in individuals with normoglycemia but not in those with prediabetes or T2D. IL-33 was directly associated with ST2, CD302, fibrinogen-like protein 2 (FGL2), and PR domain containing 16 (PRDM16) but inversely correlated with chemokine (C-C motif) ligand (CCL) 7 and CCL8 in individuals with normoglycemia. Similarly, IL-33 was directly associated with ST2, CD302, FGL2, PRDM16, and, additionally, toll-like receptor (TLR) 3 and IL-12A in individuals with T2D. However, IL-33 was not associated with any of these mediators but was directly and strongly associated with TLR9 in individuals with prediabetes. Conclusions IL-33 and/or IL-33/ST2 dynamics and biological functions may play a role in overall glycemia among humans and may represent a novel target by which glucose-lowering managements confer their beneficial effects.
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