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Gamboa Marin OJ, Adda‐Bouchard Y, Sylla B, Verma N, Charpentier T, Huber M, Lopez G, Pichette A, Lamarre A, Gauthier C. Immunological and Toxicological Assessment of Triterpenoid Saponins Bearing Lewis-X- and QS-21-Based Trisaccharides. Chemistry 2025; 31:e202500994. [PMID: 40192644 PMCID: PMC12089902 DOI: 10.1002/chem.202500994] [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: 03/12/2025] [Revised: 04/03/2025] [Accepted: 04/04/2025] [Indexed: 04/22/2025]
Abstract
The search for safer and more effective vaccine adjuvants has intensified in recent years, with triterpenoid saponins like QS-21 and its analogues emerging as promising candidates. We report the synthesis of a novel QS-21 analogue featuring betulinic acid as aglycone, a lupane-type triterpenoid with low toxicity derived from white birch bark. Two convergent synthetic routes, involving different protecting groups and glycosyl donors (bromide and trichloroacetimidate), were optimized to construct the QS-21-based linear trisaccharide motif critical for adjuvant activity. This strategy also enabled efficient preparation of the structurally similar echinocystic acid analogue reported by Gin. The immunological and toxicological profiles of these chimeric saponins, along with Lewis-X-containing and rhamnose-modified derivatives, were evaluated in C57BL/6 wild-type and hDC-SIGN transgenic mice. While the synthetic saponins exhibited low toxicity in vitro and in vivo, replacing echinocystic acid with betulinic acid reduced immunogenicity when tested with ovalbumin as a model antigen compared to alhydrogel and QS-21. These findings provide a foundation for developing saponin-based adjuvants and demonstrate the utility of advanced glycosylation strategies for synthesizing complex unnatural triterpenoid saponins.
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Affiliation(s)
- Oscar Javier Gamboa Marin
- Centre Armand‐Frappier Santé BiotechnologieInstitut National de la Recherche Scientifique (INRS)LavalQuébecH7V 1B7Canada
- Unité Mixte de Recherche (UMR) INRS‐UQACInstitut National de la Recherche Scientifique (INRS)ChicoutimiQuébecG7H 2B1Canada
| | - Yasmine Adda‐Bouchard
- Centre Armand‐Frappier Santé BiotechnologieInstitut National de la Recherche Scientifique (INRS)LavalQuébecH7V 1B7Canada
| | - Balla Sylla
- Laboratoire LASEVEDépartement des Sciences FondamentalesUniversité du Québec à Chicoutimi (UQAC)ChicoutimiQuébecG7H 2B1Canada
| | - Nitish Verma
- Centre Armand‐Frappier Santé BiotechnologieInstitut National de la Recherche Scientifique (INRS)LavalQuébecH7V 1B7Canada
- Unité Mixte de Recherche (UMR) INRS‐UQACInstitut National de la Recherche Scientifique (INRS)ChicoutimiQuébecG7H 2B1Canada
| | - Tania Charpentier
- Centre Armand‐Frappier Santé BiotechnologieInstitut National de la Recherche Scientifique (INRS)LavalQuébecH7V 1B7Canada
| | - Maya Huber
- Centre Armand‐Frappier Santé BiotechnologieInstitut National de la Recherche Scientifique (INRS)LavalQuébecH7V 1B7Canada
| | - Guillaume Lopez
- Centre Armand‐Frappier Santé BiotechnologieInstitut National de la Recherche Scientifique (INRS)LavalQuébecH7V 1B7Canada
| | - André Pichette
- Laboratoire LASEVEDépartement des Sciences FondamentalesUniversité du Québec à Chicoutimi (UQAC)ChicoutimiQuébecG7H 2B1Canada
| | - Alain Lamarre
- Centre Armand‐Frappier Santé BiotechnologieInstitut National de la Recherche Scientifique (INRS)LavalQuébecH7V 1B7Canada
| | - Charles Gauthier
- Centre Armand‐Frappier Santé BiotechnologieInstitut National de la Recherche Scientifique (INRS)LavalQuébecH7V 1B7Canada
- Unité Mixte de Recherche (UMR) INRS‐UQACInstitut National de la Recherche Scientifique (INRS)ChicoutimiQuébecG7H 2B1Canada
- Laboratoire LASEVEDépartement des Sciences FondamentalesUniversité du Québec à Chicoutimi (UQAC)ChicoutimiQuébecG7H 2B1Canada
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Martínez JD, Núñez-Franco R, Valverde P, Delgado S, Ardá A, Jiménez-Barbero J, Jiménez-Oses G, Cañada FJ. Glycans and Chirality: Stereoselectivity at the Core of DC-SIGN's Recognition. A Novel View of the Optimum Minimal Ligand Epitope. Chemistry 2025:e202501420. [PMID: 40342067 DOI: 10.1002/chem.202501420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2025] [Revised: 05/07/2025] [Accepted: 05/07/2025] [Indexed: 05/11/2025]
Abstract
Glycans exhibit an unparalleled density of stereochemical information, encoded at the monosaccharide level through multiple stereogenic centers, anomeric configurations, ring tautomerism, and conformational variability. Indeed, chiral recognition is fundamental to the interaction between glycans and proteins. Despite the theoretical risk posed by mirror-image molecules, the stereochemical diversity of the "glycan code" enables similar chiral motifs to arise from both D- and L-sugars. Herein, we present an in-depth investigation of the stereochemical features governing lectin-glycan recognition, using the well-characterized human C-type lectin Dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN) as a model. By combining experimental (STD-NMR) and computational approaches, we identified a minimal optimal binding epitope recognized by DC-SIGN. Key binding requirements include the correct chirality of the Ca2⁺-coordinating oxygens, an adjacent equatorial hydroxyl group for hydrogen bonding with Glu354, and hydrophobic contacts with Val351. Known ligands L-fucose and D-mannose fulfill these criteria. Our results further demonstrate that DC-SIGN also binds α/β-L-galactose, α/β-D-rhamnose, and myo-inositol. Among these, α/β-D-rhamnose exhibits higher affinity than α-OMe-D-mannose, while α/β-L-galactose binds more strongly than D-rhamnose and myo-inositol, although with lower affinity than α-OMe-L-fucose. STD-NMR experiments confirmed that all these ligands share the same core binding epitope.
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Affiliation(s)
- J Daniel Martínez
- Centro de Investigaciones Biológicas Margarita Salas, CSIC, Ramiro de Maeztu 9, 28040, Madrid, Spain
| | - Reyes Núñez-Franco
- CIC bioGUNE, Basque Research Technology Alliance, BRTA, Bizkaia Technology park, Building 800, 48160, Derio, Spain
| | - Pablo Valverde
- Centro de Investigaciones Biológicas Margarita Salas, CSIC, Ramiro de Maeztu 9, 28040, Madrid, Spain
- CIC bioGUNE, Basque Research Technology Alliance, BRTA, Bizkaia Technology park, Building 800, 48160, Derio, Spain
| | - Sandra Delgado
- CIC bioGUNE, Basque Research Technology Alliance, BRTA, Bizkaia Technology park, Building 800, 48160, Derio, Spain
| | - Ana Ardá
- CIC bioGUNE, Basque Research Technology Alliance, BRTA, Bizkaia Technology park, Building 800, 48160, Derio, Spain
- Ikerbasque, Basque Foundation for Science, 48013, Bilbao, Spain
| | - Jesús Jiménez-Barbero
- CIC bioGUNE, Basque Research Technology Alliance, BRTA, Bizkaia Technology park, Building 800, 48160, Derio, Spain
- Ikerbasque, Basque Foundation for Science, 48013, Bilbao, Spain
- Department of Organic Chemistry II Faculty of Science and Technology University of the Basque Country, EHU-UPV, Leioa, Spain
- CIBER de Enfermedades Respiratorias (CIBERES) Avda, Monforte de Lemos 3-5, 28029, Madrid, Spain
| | - Gonzalo Jiménez-Oses
- CIC bioGUNE, Basque Research Technology Alliance, BRTA, Bizkaia Technology park, Building 800, 48160, Derio, Spain
- Ikerbasque, Basque Foundation for Science, 48013, Bilbao, Spain
| | - F Javier Cañada
- Centro de Investigaciones Biológicas Margarita Salas, CSIC, Ramiro de Maeztu 9, 28040, Madrid, Spain
- CIBER de Enfermedades Respiratorias (CIBERES) Avda, Monforte de Lemos 3-5, 28029, Madrid, Spain
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Vlaming KE, Jansen J, de Bree GJ, Kootstra NA, Geijtenbeek TBH. Synergistic Activity of Second Mitochondrial-Derived Activator of Caspases Mimetic with Toll-like Receptor 8 Agonist Reverses HIV-1-Latency and Enhances Antiviral Immunity. Int J Mol Sci 2025; 26:2575. [PMID: 40141220 PMCID: PMC11941979 DOI: 10.3390/ijms26062575] [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: 02/14/2025] [Revised: 03/07/2025] [Accepted: 03/11/2025] [Indexed: 03/28/2025] Open
Abstract
HIV-1 infection is successfully treated by antiretroviral therapy; however, it is not curative as HIV-1 remains present in the viral reservoir. A strategy to eliminate the viral reservoir relies on the reactivation of the latent provirus to subsequently trigger immune-mediated clearance. Here, we investigated whether the activation of Toll-like receptor 8 (TLR8) or RIG-I-like receptor (RLR) together with the latency reversal agent (LRA) second mitochondrial-derived activator of caspases mimetics (SMACm) leads to HIV-1 reservoir reduction and antiviral immune activation. The TLR8 and RLR agonist elicited a robust pro-inflammatory cytokine response in PBMCs from both PWH and uninfected people. Notably, co-stimulation with SMACm specifically enhanced TLR8 induced pro-inflammatory cytokine as well as CD8 T cell responses. Ex vivo treatment of PBMCs from PWH with SMACm significantly decreased the size of the inducible HIV-1 reservoir, whereas targeting TLR8 or RLR reduced the HIV-1 reservoir in 50% of PWH ex vivo. Although co-stimulation with TLR8/RLR agonists further reduced the HIV-1 reservoir in 25% of PWH ex vivo, effectively inducing antiviral immunity may help eliminate reactivated HIV-1 cells in vivo. Our findings strongly suggest that LRAs can be used in combination with agonists for pattern recognition receptors to reactivate HIV-1 and induce antiviral immunity.
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Affiliation(s)
- Killian E. Vlaming
- Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
- Amsterdam Institute for Immunology and Infectious Diseases, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Jade Jansen
- Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
- Amsterdam Institute for Immunology and Infectious Diseases, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Godelieve J. de Bree
- Amsterdam Institute for Immunology and Infectious Diseases, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
- Department of Internal Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Neeltje A. Kootstra
- Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
- Amsterdam Institute for Immunology and Infectious Diseases, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Teunis B. H. Geijtenbeek
- Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
- Amsterdam Institute for Immunology and Infectious Diseases, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
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Decout A, Krasias I, Roberts L, Gimeno Molina B, Charenton C, Brown Romero D, Tee QY, Marchesi JR, Ng S, Sykes L, Bennett PR, MacIntyre DA. Lactobacillus crispatus S-layer proteins modulate innate immune response and inflammation in the lower female reproductive tract. Nat Commun 2024; 15:10879. [PMID: 39737998 PMCID: PMC11685708 DOI: 10.1038/s41467-024-55233-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 12/04/2024] [Indexed: 01/01/2025] Open
Abstract
Lactobacillus species dominance of the vaginal microbiome is a hallmark of vaginal health. Pathogen displacement of vaginal lactobacilli drives innate immune activation and mucosal barrier disruption, increasing the risks of STI acquisition and, in pregnancy, of preterm birth. We describe differential TLR mediated activation of the proinflammatory transcription factor NF-κB by vaginal pathogens and commensals. Vaginal Lactobacillus strains associated with optimal health selectively interact with anti-inflammatory innate immune receptors whereas species associated with suboptimal health including L. iners and Gardnerella vaginalis interact with both pro- and anti-inflammatory receptors. Anti-inflammatory action of L. crispatus is regulated by surface layer protein (SLPs)-mediated shielding of TLR ligands and selective interaction with the anti-inflammatory receptor DC-SIGN. Detection of SLPs within cervicovaginal fluid samples is associated with decreased concentrations of pro-inflammatory cytokines in Lactobacillus crispatus-dominated samples. These data offer mechanistic insights into how vaginal microbiota modulate host immune response and thus reproductive health and disease states.
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Affiliation(s)
- Alexiane Decout
- Imperial College Parturition Research Group, Institute of Reproductive and Developmental Biology, Department of Metabolism Digestion and Reproduction, Imperial College London, London, UK.
| | - Ioannis Krasias
- Imperial College Parturition Research Group, Institute of Reproductive and Developmental Biology, Department of Metabolism Digestion and Reproduction, Imperial College London, London, UK
| | - Lauren Roberts
- Imperial College Parturition Research Group, Institute of Reproductive and Developmental Biology, Department of Metabolism Digestion and Reproduction, Imperial College London, London, UK
- March of Dimes Prematurity Research Centre at Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, UK
- Division of Digestive Diseases, Department of Metabolism, Digestion, and Reproduction, St Mary's Hospital Campus, Imperial College London, London, UK
| | - Belen Gimeno Molina
- Imperial College Parturition Research Group, Institute of Reproductive and Developmental Biology, Department of Metabolism Digestion and Reproduction, Imperial College London, London, UK
- March of Dimes Prematurity Research Centre at Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, UK
- The Parasol Foundation Centre for Women's Health and Cancer Research, London, UK
| | - Chloé Charenton
- Imperial College Parturition Research Group, Institute of Reproductive and Developmental Biology, Department of Metabolism Digestion and Reproduction, Imperial College London, London, UK
| | - Daniel Brown Romero
- Imperial College Parturition Research Group, Institute of Reproductive and Developmental Biology, Department of Metabolism Digestion and Reproduction, Imperial College London, London, UK
| | - Qiong Y Tee
- Imperial College Parturition Research Group, Institute of Reproductive and Developmental Biology, Department of Metabolism Digestion and Reproduction, Imperial College London, London, UK
| | - Julian R Marchesi
- March of Dimes Prematurity Research Centre at Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, UK
- Division of Digestive Diseases, Department of Metabolism, Digestion, and Reproduction, St Mary's Hospital Campus, Imperial College London, London, UK
| | - Sherrianne Ng
- Imperial College Parturition Research Group, Institute of Reproductive and Developmental Biology, Department of Metabolism Digestion and Reproduction, Imperial College London, London, UK
- March of Dimes Prematurity Research Centre at Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, UK
| | - Lynne Sykes
- Imperial College Parturition Research Group, Institute of Reproductive and Developmental Biology, Department of Metabolism Digestion and Reproduction, Imperial College London, London, UK
- March of Dimes Prematurity Research Centre at Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, UK
- The Parasol Foundation Centre for Women's Health and Cancer Research, London, UK
| | - Phillip R Bennett
- Imperial College Parturition Research Group, Institute of Reproductive and Developmental Biology, Department of Metabolism Digestion and Reproduction, Imperial College London, London, UK
- March of Dimes Prematurity Research Centre at Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, UK
| | - David A MacIntyre
- Imperial College Parturition Research Group, Institute of Reproductive and Developmental Biology, Department of Metabolism Digestion and Reproduction, Imperial College London, London, UK
- March of Dimes Prematurity Research Centre at Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, UK
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Sun X, Wu H, Tang L, Al-Danakh A, Jian Y, Gong L, Li C, Yu X, Zeng G, Chen Q, Yang D, Wang S. GALNT6 promotes bladder cancer malignancy and immune escape by epithelial-mesenchymal transition and CD8 + T cells. Cancer Cell Int 2024; 24:308. [PMID: 39245709 PMCID: PMC11382498 DOI: 10.1186/s12935-024-03492-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 08/28/2024] [Indexed: 09/10/2024] Open
Abstract
Bladder cancer (BC) ranks as the sixth cancer in males and the ninth most common cancer worldwide. Conventional treatment modalities, including surgery, radiation, chemotherapy, and immunotherapy, have limited efficacy in certain advanced instances. The involvement of GALNT6-mediated aberrant O-glycosylation modification in several malignancies and immune evasion is a subject of speculation. However, its significance in BC has not been investigated. Through the integration of bioinformatics analysis and laboratory experimentation, we have successfully clarified the role of GALNT6 in BC. Our investigation revealed that GALNT6 has significant expression in BC, and its high expression level correlates with advanced stage and high grade, leading to poor overall survival. Moreover, both in vitro and in vivo experiments demonstrate a strong correlation between elevated levels of GALNT6 and tumor growth, migration, and invasion. Furthermore, there is a negative correlation between elevated GALNT6 levels, the extent of CD8+ T cell infiltration in the tumor microenvironment, and the prognosis of patients. Functional experiments have shown that the increased expression of GALNT6 could enhance the malignant characteristics of cancer cells by activating the epithelial-mesenchymal transition (EMT) pathway. In brief, this study examined the impact of GALNT6-mediated abnormal O-glycosylation on the occurrence and progression of bladder cancer and its influence on immune evasion. It also explored the possible molecular mechanism underlying the interaction between tumor cells and immune cells, as well as the bidirectional signaling involved. These findings offer a novel theoretical foundation rooted in glycobiology for the clinical application of immunotherapy in BC.
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Affiliation(s)
- Xiaoxin Sun
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
- College of Integrative Medicine, Dalian Medical University, Dalian, 116044, China
| | - Haotian Wu
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Ling Tang
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Abdullah Al-Danakh
- Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian, 116000, China
| | - Yuli Jian
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Li Gong
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Congchen Li
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Xiao Yu
- Department of Pathology and Forensic Medicine, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China
| | - Guang Zeng
- College of Integrative Medicine, Dalian Medical University, Dalian, 116044, China
| | - Qiwei Chen
- Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian, 116000, China.
- Zhongda Hospital, Medical School, Advanced Institute for Life and Health, Southeast University, 210096, Nanjing, China.
| | - Deyong Yang
- Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian, 116000, China.
| | - Shujing Wang
- Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China.
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Debreceni IL, Barr JY, Upton EM, Chen YG, Lieberman SM. IL-27 promotes pathogenic T cells in a mouse model of Sjögren's disease. Clin Immunol 2024; 264:110260. [PMID: 38788885 PMCID: PMC11203157 DOI: 10.1016/j.clim.2024.110260] [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: 11/02/2023] [Revised: 03/25/2024] [Accepted: 05/21/2024] [Indexed: 05/26/2024]
Abstract
Sjögren's disease (SjD) is a chronic autoimmune disease characterized by focal lymphocytic inflammation in lacrimal and salivary glands. We recently identified IL-27 as a requisite signal for the spontaneous SjD-like manifestations in nonobese diabetic (NOD) mice. Here, we define T cell-intrinsic effects of IL-27 in lacrimal gland disease in NOD mice. IL-27 receptor was required by both CD4 T effector (Te) cells and CD8 T cells to mediate focal inflammation. Intrinsic IL-27 signaling was associated with PD-1 and ICOS expressing T follicular helper (Tfh)-like CD4 Te cells within lacrimal glands, including subsets defined by CD73 or CD39 expression. CD8 T cells capable of IL-27 signaling also expressed PD-1 with subsets expressing ICOS and CD73 demonstrating a T follicular cytotoxic (Tfc)-like cell phenotype and others expressing a CD39hi exhausted-like phenotype. These findings suggest IL-27 is a key early signal driving a follicular-type response in lacrimal gland inflammation in NOD mice.
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Affiliation(s)
- Ivy L Debreceni
- Interdisciplinary Graduate Program in Immunology, Carver College of Medicine, University of Iowa, 500 Newton Road, 2191 Medical Laboratories, Iowa City, IA 52242, USA; Stead Family Department of Pediatrics, Carver College of Medicine, University of Iowa, 500 Newton Road, 2191 Medical Laboratories, Iowa City, IA 52242, USA.
| | - Jennifer Y Barr
- Scientific Editing and Research Communication Core, Carver College of Medicine, University of Iowa, 451 Newton Road, 130 Medicine Administration Building, Iowa City, IA 52242, USA.
| | - Ellen M Upton
- Interdisciplinary Graduate Program in Immunology, Carver College of Medicine, University of Iowa, 500 Newton Road, 2191 Medical Laboratories, Iowa City, IA 52242, USA; Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, 451 Newton Road, 200 Medicine Administration Building, Iowa City, IA 52242, USA.
| | - Yi-Guang Chen
- Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
| | - Scott M Lieberman
- Interdisciplinary Graduate Program in Immunology, Carver College of Medicine, University of Iowa, 500 Newton Road, 2191 Medical Laboratories, Iowa City, IA 52242, USA; Stead Family Department of Pediatrics, Carver College of Medicine, University of Iowa, 500 Newton Road, 2191 Medical Laboratories, Iowa City, IA 52242, USA.
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7
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Burton C, Bitaraf A, Snyder K, Zhang C, Yoder SJ, Avram D, Du D, Yu X, Lau EK. The functional role of L-fucose on dendritic cell function and polarization. Front Immunol 2024; 15:1353570. [PMID: 38646527 PMCID: PMC11026564 DOI: 10.3389/fimmu.2024.1353570] [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: 12/10/2023] [Accepted: 02/21/2024] [Indexed: 04/23/2024] Open
Abstract
Despite significant advances in the development and refinement of immunotherapies administered to combat cancer over the past decades, a number of barriers continue to limit their efficacy. One significant clinical barrier is the inability to mount initial immune responses towards the tumor. As dendritic cells are central initiators of immune responses in the body, the elucidation of mechanisms that can be therapeutically leveraged to enhance their functions to drive anti-tumor immune responses is urgently needed. Here, we report that the dietary sugar L-fucose can be used to enhance the immunostimulatory activity of dendritic cells (DCs). L-fucose polarizes immature myeloid cells towards specific DC subsets, specifically cDC1 and moDC subsets. In vitro, L-fucose treatment enhances antigen uptake and processing of DCs. Furthermore, our data suggests that L-fucose-treated DCs increase stimulation of T cell populations. Consistent with our functional assays, single-cell RNA sequencing of intratumoral DCs from melanoma- and breast tumor-bearing mice confirmed transcriptional regulation and antigen processing as pathways that are significantly altered by dietary L-fucose. Together, this study provides the first evidence of the ability of L-fucose to bolster DC functionality and provides rational to further investigate how L-fucose can be used to leverage DC function in order to enhance current immunotherapy.
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Affiliation(s)
- Chase Burton
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
- Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, United States
- Immunology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Amirreza Bitaraf
- Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, United States
- Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
- Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Kara Snyder
- Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
- Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
- Department of Molecular Medicine, University of South Florida, Tampa, FL, United States
| | - Chaomei Zhang
- Molecular Genomics Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Sean J. Yoder
- Molecular Genomics Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Dorina Avram
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
- Immunology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Dongliang Du
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Xiaoqing Yu
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Eric K. Lau
- Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
- Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
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8
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Kamii Y, Hayashizaki K, Kanno T, Chiba A, Ikegami T, Saito M, Akeda Y, Ohteki T, Kubo M, Yoshida K, Kawakami K, Oishi K, Araya J, Kuwano K, Kronenberg M, Endo Y, Kinjo Y. IL-27 regulates the differentiation of follicular helper NKT cells via metabolic adaptation of mitochondria. Proc Natl Acad Sci U S A 2024; 121:e2313964121. [PMID: 38394242 PMCID: PMC10907256 DOI: 10.1073/pnas.2313964121] [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: 08/18/2023] [Accepted: 01/12/2024] [Indexed: 02/25/2024] Open
Abstract
Invariant natural killer T (iNKT) cells are innate-like T lymphocytes that express an invariant T cell receptor α chain and contribute to bridging innate and acquired immunity with rapid production of large amounts of cytokines after stimulation. Among effecter subsets of iNKT cells, follicular helper NKT (NKTFH) cells are specialized to help B cells. However, the mechanisms of NKTFH cell differentiation remain to be elucidated. In this report, we studied the mechanism of NKTFH cell differentiation induced by pneumococcal surface protein A and α-galactosylceramide (P/A) vaccination. We found that Gr-1+ cells helped iNKT cell proliferation and NKTFH cell differentiation in the spleen by producing interleukin-27 (IL-27) in the early phase after vaccination. The neutralization of IL-27 impaired NKTFH cell differentiation, which resulted in compromised antibody production and diminished protection against Streptococcus pneumoniae infection by the P/A vaccine. Our data indicated that Gr-1+ cell-derived IL-27 stimulated mitochondrial metabolism, meeting the energic demand required for iNKT cells to differentiate into NKTFH cells. Interestingly, Gr-1+ cell-derived IL-27 was induced by iNKT cells via interferon-γ production. Collectively, our findings suggest that optimizing the metabolism of iNKT cells was essential for acquiring specific effector functions, and they provide beneficial knowledge on iNKT cell-mediated vaccination-mediated therapeutic strategies.
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Affiliation(s)
- Yasuhiro Kamii
- Department of Bacteriology, The Jikei University School of Medicine, Tokyo105-8461, Japan
- Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo105-8461, Japan
| | - Koji Hayashizaki
- Department of Bacteriology, The Jikei University School of Medicine, Tokyo105-8461, Japan
- Jikei Center for Biofilm Science and Technology, The Jikei University School of Medicine, Tokyo105-8461, Japan
| | - Toshio Kanno
- Department of Frontier Research and Development, Laboratory of Medical Omics Research, Kazusa DNA Research Institute, Chiba292-0818, Japan
| | - Akio Chiba
- Department of Bacteriology, The Jikei University School of Medicine, Tokyo105-8461, Japan
- Jikei Center for Biofilm Science and Technology, The Jikei University School of Medicine, Tokyo105-8461, Japan
| | - Taku Ikegami
- Department of Bacteriology, The Jikei University School of Medicine, Tokyo105-8461, Japan
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, Tokyo105-8461, Japan
| | - Mitsuru Saito
- Department of Orthopaedic Surgery, The Jikei University School of Medicine, Tokyo105-8461, Japan
| | - Yukihiro Akeda
- Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo162-8640, Japan
| | - Toshiaki Ohteki
- Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University, Tokyo113-8510, Japan
| | - Masato Kubo
- Division of Molecular Pathology, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba278-0022, Japan
| | - Kiyotsugu Yoshida
- Department of Biochemistry, The Jikei University School of Medicine, Tokyo105-8461, Japan
| | - Kazuyoshi Kawakami
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Miyagi980-8575, Japan
| | | | - Jun Araya
- Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo105-8461, Japan
| | - Kazuyoshi Kuwano
- Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo105-8461, Japan
| | - Mitchell Kronenberg
- La Jolla Institute for Immunology, La Jolla, CA92037
- Department of Molecular Biology, University of California, San Diego, La Jolla, CA92093
| | - Yusuke Endo
- Department of Frontier Research and Development, Laboratory of Medical Omics Research, Kazusa DNA Research Institute, Chiba292-0818, Japan
| | - Yuki Kinjo
- Department of Bacteriology, The Jikei University School of Medicine, Tokyo105-8461, Japan
- Jikei Center for Biofilm Science and Technology, The Jikei University School of Medicine, Tokyo105-8461, Japan
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9
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Lake BM, Rullo AF. Offsetting Low-Affinity Carbohydrate Binding with Covalency to Engage Sugar-Specific Proteins for Tumor-Immune Proximity Induction. ACS CENTRAL SCIENCE 2023; 9:2064-2075. [PMID: 38033792 PMCID: PMC10683482 DOI: 10.1021/acscentsci.3c01052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Indexed: 12/02/2023]
Abstract
Carbohydrate-binding receptors are often used by the innate immune system to potentiate inflammation, target endocytosis/destruction, and adaptive immunity (e.g., CD206, DC-SIGN, MBL, and anticarbohydrate antibodies). To access this class of receptors for cancer immunotherapy, a growing repertoire of bifunctional proximity-inducing therapeutics use high-avidity multivalent carbohydrate binding domains to offset the intrinsically low affinity associated with monomeric carbohydrate-protein binding interactions (Kd ≈ 10-3-10-6 M). For applications aimed at recruiting anticarbohydrate antibodies to tumor cells, large synthetic scaffolds are used that contain both a tumor-binding domain (TBD) and a multivalent antibody-binding domain (ABD) comprising multiple l-rhamnose monosaccharides. This allows for stable bridging between tumor cells and antibodies, which activates tumoricidal immune function. Problematically, such multivalent macromolecules can face limitations including synthetic and/or structural complexity and the potential for off-target immune engagement. We envisioned that small bifunctional "proximity-inducing" molecules containing a low-affinity monovalent ABD could efficiently engage carbohydrate-binding receptors for tumor-immune proximity by coupling weak binding with covalent engagement. Typical covalent drugs and electrophilic chimeras use high-affinity ligands to promote the fast covalent engagement of target proteins (i.e., large kinact/KI), driven by a favorably small KI for binding. We hypothesized the much less favorable KI associated with carbohydrate-protein binding interactions can be offset by a favorably large kinact for the covalent labeling step. In the current study, we test this hypothesis in the context of a model system that uses rhamnose-specific antibodies to induce tumor-immune proximity and tumoricidal function. We discovered that synthetic chimeric molecules capable of preorganizing an optimal electrophile (i.e., SuFEx vs activated ester) for protein engagement can rapidly covalently engage natural sources of antirhamnose antibody using only a single low-affinity rhamnose monosaccharide ABD. Strikingly, we observe chimeric molecules lacking an electrophile, which can only noncovalently bind the antibody, completely lack tumoricidal function. This is in stark contrast to previous work targeting small molecule hapten and peptide-specific antibodies. Our findings underscore the utility of covalency as a strategy to engage low-affinity carbohydrate-specific proteins for tumor-immune proximity induction.
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Affiliation(s)
- Benjamin
P. M. Lake
- Department
of Medicine, McMaster Immunology Research Center, Center
for Discovery in Cancer Research, Department of Biochemistry and Biomedical
Sciences, and Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton Ontario, Canada
| | - Anthony F. Rullo
- Department
of Medicine, McMaster Immunology Research Center, Center
for Discovery in Cancer Research, Department of Biochemistry and Biomedical
Sciences, and Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton Ontario, Canada
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10
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Pereira EPV, da Silva Felipe SM, de Freitas RM, da Cruz Freire JE, Oliveira AER, Canabrava N, Soares PM, van Tilburg MF, Guedes MIF, Grueter CE, Ceccatto VM. Transcriptional Profiling of SARS-CoV-2-Infected Calu-3 Cells Reveals Immune-Related Signaling Pathways. Pathogens 2023; 12:1373. [PMID: 38003837 PMCID: PMC10674242 DOI: 10.3390/pathogens12111373] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 11/11/2023] [Accepted: 11/14/2023] [Indexed: 11/26/2023] Open
Abstract
The COVID-19 disease, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), emerged in late 2019 and rapidly spread worldwide, becoming a pandemic that infected millions of people and caused significant deaths. COVID-19 continues to be a major threat, and there is a need to deepen our understanding of the virus and its mechanisms of infection. To study the cellular responses to SARS-CoV-2 infection, we performed an RNA sequencing of infected vs. uninfected Calu-3 cells. Total RNA was extracted from infected (0.5 MOI) and control Calu-3 cells and converted to cDNA. Sequencing was performed, and the obtained reads were quality-analyzed and pre-processed. Differential expression was assessed with the EdgeR package, and functional enrichment was performed in EnrichR for Gene Ontology, KEGG pathways, and WikiPathways. A total of 1040 differentially expressed genes were found in infected vs. uninfected Calu-3 cells, of which 695 were up-regulated and 345 were down-regulated. Functional enrichment analyses revealed the predominant up-regulation of genes related to innate immune response, response to virus, inflammation, cell proliferation, and apoptosis. These transcriptional changes following SARS-CoV-2 infection may reflect a cellular response to the infection and help to elucidate COVID-19 pathogenesis, in addition to revealing potential biomarkers and drug targets.
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Affiliation(s)
- Eric Petterson Viana Pereira
- Superior Institute of Biomedical Sciences, State University of Ceará, Fortaleza 60714-903, CE, Brazil; (S.M.d.S.F.); (R.M.d.F.); (J.E.d.C.F.); (P.M.S.)
| | - Stela Mirla da Silva Felipe
- Superior Institute of Biomedical Sciences, State University of Ceará, Fortaleza 60714-903, CE, Brazil; (S.M.d.S.F.); (R.M.d.F.); (J.E.d.C.F.); (P.M.S.)
| | - Raquel Martins de Freitas
- Superior Institute of Biomedical Sciences, State University of Ceará, Fortaleza 60714-903, CE, Brazil; (S.M.d.S.F.); (R.M.d.F.); (J.E.d.C.F.); (P.M.S.)
| | - José Ednésio da Cruz Freire
- Superior Institute of Biomedical Sciences, State University of Ceará, Fortaleza 60714-903, CE, Brazil; (S.M.d.S.F.); (R.M.d.F.); (J.E.d.C.F.); (P.M.S.)
| | | | - Natália Canabrava
- Biotechnology and Molecular Biology Laboratory, State University of Ceará, Fortaleza 60714-903, CE, Brazil; (N.C.); (M.F.v.T.); (M.I.F.G.)
| | - Paula Matias Soares
- Superior Institute of Biomedical Sciences, State University of Ceará, Fortaleza 60714-903, CE, Brazil; (S.M.d.S.F.); (R.M.d.F.); (J.E.d.C.F.); (P.M.S.)
| | - Mauricio Fraga van Tilburg
- Biotechnology and Molecular Biology Laboratory, State University of Ceará, Fortaleza 60714-903, CE, Brazil; (N.C.); (M.F.v.T.); (M.I.F.G.)
| | - Maria Izabel Florindo Guedes
- Biotechnology and Molecular Biology Laboratory, State University of Ceará, Fortaleza 60714-903, CE, Brazil; (N.C.); (M.F.v.T.); (M.I.F.G.)
| | - Chad Eric Grueter
- Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA;
| | - Vânia Marilande Ceccatto
- Superior Institute of Biomedical Sciences, State University of Ceará, Fortaleza 60714-903, CE, Brazil; (S.M.d.S.F.); (R.M.d.F.); (J.E.d.C.F.); (P.M.S.)
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11
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Zhang NZ, Zhao LF, Zhang Q, Fang H, Song WL, Li WZ, Ge YS, Gao P. Core fucosylation and its roles in gastrointestinal glycoimmunology. World J Gastrointest Oncol 2023; 15:1119-1134. [PMID: 37546555 PMCID: PMC10401475 DOI: 10.4251/wjgo.v15.i7.1119] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 02/28/2023] [Accepted: 05/08/2023] [Indexed: 07/12/2023] Open
Abstract
Glycosylation is a common post-translational modification in eukaryotic cells. It is involved in the production of many biologically active glycoproteins and the regulation of protein structure and function. Core fucosylation plays a vital role in the immune response. Most immune system molecules are core fucosylated glycoproteins such as complements, cluster differentiation antigens, immunoglobulins, cytokines, major histocompatibility complex molecules, adhesion molecules, and immune molecule synthesis-related transcription factors. These core fucosylated glycoproteins play important roles in antigen recognition and clearance, cell adhesion, lymphocyte activation, apoptosis, signal transduction, and endocytosis. Core fucosylation is dominated by fucosyltransferase 8 (Fut8), which catalyzes the addition of α-1,6-fucose to the innermost GlcNAc residue of N-glycans. Fut8 is involved in humoral, cellular, and mucosal immunity. Tumor immunology is associated with aberrant core fucosylation. Here, we summarize the roles and potential modulatory mechanisms of Fut8 in various immune processes of the gastrointestinal system.
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Affiliation(s)
- Nian-Zhu Zhang
- Clinical Laboratory, The Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Li-Fen Zhao
- Clinical Laboratory, The Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Qian Zhang
- Department of Cell Therapy, Shanghai Tianze Yuntai Biomedical Co., Ltd., Shanghai 200100, China
| | - Hui Fang
- Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba 305-0005, Ibaraki, Japan
| | - Wan-Li Song
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Wen-Zhe Li
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yu-Song Ge
- Department of Neurology, The Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Peng Gao
- Clinical Laboratory, The Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
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12
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Vlaming KE, van Wijnbergen K, Kaptein TM, Nijhuis M, Kootstra NJ, de Bree GJ, Geijtenbeek TB. Crosstalk between TLR8 and RIG-I-like receptors enhances antiviral immune responses. Front Med (Lausanne) 2023; 10:1146457. [PMID: 37261119 PMCID: PMC10227620 DOI: 10.3389/fmed.2023.1146457] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 04/12/2023] [Indexed: 06/02/2023] Open
Abstract
Background Toll-like receptor (TLR) agonists have been investigated due to their potential dual effects as latency reverting agents and immune modulatory compounds in people living with HIV (PLWH). Here, we investigated whether co-stimulation of TLR7/8 agonists with RIG-I-like receptor (RLR) agonists enhances antiviral immunity. Methods Peripheral blood mononuclear cells (PBMCs) and monocyte-derived dendritic cells (DCs) were incubated with TLR and RLR-agonists for 24 h and innate and adaptive immune responses were determined (maturation markers, cytokines in supernatant, ISG expression). Results Both TLR7 and TLR8 agonists induced pro-inflammatory cytokines in DCs as well as PBMCs. TLR8 agonists were more potent in inducing cytokine responses and had a stronger effect on DC-induced immunity. Notably, while all compounds induced IL-12p70, co-stimulation with TLR8 agonists and RLR agonist polyI: C induced significantly higher levels of IL-12p70 in PBMCs. Moreover, crosstalk between TLR8 and RLR agonists induced a strong type I Interferon (IFN) response as different antiviral IFN-stimulated genes were upregulated by the combination compared to the agonists alone. Conclusion Our data strongly suggest that TLR crosstalk with RLRs leads to strong antiviral immunity as shown by induction of IL-12 and type I IFN responses in contrast to TLRs alone. Thus, co-stimulation of TLRs and RLRs might be a powerful strategy to induce reactivation of latent reservoir as well as antiviral immunity that eliminates the reactivated cells.
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Affiliation(s)
- Killian E. Vlaming
- Department of Experimental Immunology, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands
- Amsterdam Institute for Infection and Immunity, Amsterdam, Netherlands
| | - Kelly van Wijnbergen
- Department of Experimental Immunology, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands
- Amsterdam Institute for Infection and Immunity, Amsterdam, Netherlands
| | - Tanja M. Kaptein
- Department of Experimental Immunology, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands
- Amsterdam Institute for Infection and Immunity, Amsterdam, Netherlands
| | - Monique Nijhuis
- Translational Virology, Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Neeltje J. Kootstra
- Department of Experimental Immunology, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands
- Amsterdam Institute for Infection and Immunity, Amsterdam, Netherlands
| | - Godelieve J. de Bree
- Department of Internal Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands
| | - Teunis B. Geijtenbeek
- Department of Experimental Immunology, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands
- Amsterdam Institute for Infection and Immunity, Amsterdam, Netherlands
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13
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Solé P, Yamanouchi J, Garnica J, Uddin MM, Clarke R, Moro J, Garabatos N, Thiessen S, Ortega M, Singha S, Mondal D, Fandos C, Saez-Rodriguez J, Yang Y, Serra P, Santamaria P. A T follicular helper cell origin for T regulatory type 1 cells. Cell Mol Immunol 2023; 20:489-511. [PMID: 36973489 PMCID: PMC10202951 DOI: 10.1038/s41423-023-00989-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 02/12/2023] [Indexed: 03/29/2023] Open
Abstract
Chronic antigenic stimulation can trigger the differentiation of antigen-experienced CD4+ T cells into T regulatory type 1 (TR1) cells, a subset of interleukin-10-producing Treg cells that do not express FOXP3. The identities of the progenitor(s) and transcriptional regulators of this T-cell subset remain unclear. Here, we show that the peptide-major histocompatibility complex class II (pMHCII) monospecific immunoregulatory T-cell pools that arise in vivo in different genetic backgrounds in response to pMHCII-coated nanoparticles (pMHCII-NPs) are invariably comprised of oligoclonal subpools of T follicular helper (TFH) and TR1 cells with a nearly identical clonotypic composition but different functional properties and transcription factor expression profiles. Pseudotime analyses of scRNAseq data and multidimensional mass cytometry revealed progressive downregulation and upregulation of TFH and TR1 markers, respectively. Furthermore, pMHCII-NPs trigger cognate TR1 cell formation in TFH cell-transfused immunodeficient hosts, and T-cell-specific deletion of Bcl6 or Irf4 blunts both the TFH expansion and TR1 formation induced by pMHCII-NPs. In contrast, deletion of Prdm1 selectively abrogates the TFH-to-TR1 conversion. Bcl6 and Prdm1 are also necessary for anti-CD3 mAb-induced TR1 formation. Thus, TFH cells can differentiate into TR1 cells in vivo, and BLIMP1 is a gatekeeper of this cellular reprogramming event.
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Affiliation(s)
- Patricia Solé
- Institut D'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| | - Jun Yamanouchi
- Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Josep Garnica
- Institut D'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| | - Muhammad Myn Uddin
- Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Robert Clarke
- Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Joel Moro
- Institut D'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| | - Nahir Garabatos
- Institut D'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| | - Shari Thiessen
- Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Mireia Ortega
- Institut D'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| | - Santiswarup Singha
- Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Debajyoti Mondal
- Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - César Fandos
- Institut D'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| | - Julio Saez-Rodriguez
- Institute of Computational Biomedicine, Faculty of Medicine, Heidelberg University, Heidelberg, Germany
| | - Yang Yang
- Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Pau Serra
- Institut D'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| | - Pere Santamaria
- Institut D'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
- Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
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14
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Antonarelli G, Pieri V, Porta FM, Fusco N, Finocchiaro G, Curigliano G, Criscitiello C. Targeting Post-Translational Modifications to Improve Combinatorial Therapies in Breast Cancer: The Role of Fucosylation. Cells 2023; 12:cells12060840. [PMID: 36980181 PMCID: PMC10047715 DOI: 10.3390/cells12060840] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/03/2023] [Accepted: 03/05/2023] [Indexed: 03/30/2023] Open
Abstract
Various tumors rely on post-translational modifications (PTMs) to promote invasiveness and angiogenesis and to reprogram cellular energetics to abate anti-cancer immunity. Among PTMs, fucosylation is a particular type of glycosylation that has been linked to different aspects of immune and hormonal physiological functions as well as hijacked by many types of tumors. Multiple tumors, including breast cancer, have been linked to dismal prognoses and increased metastatic potential due to fucosylation of the glycan core, namely core-fucosylation. Pre-clinical studies have examined the molecular mechanisms regulating core-fucosylation in breast cancer models, its negative prognostic value across multiple disease stages, and the activity of in vivo pharmacological inhibition, instructing combinatorial therapies and translation into clinical practice. Throughout this review, we describe the role of fucosylation in solid tumors, with a particular focus on breast cancer, as well as physiologic conditions on the immune system and hormones, providing a view into its potential as a biomarker for predicating or predicting cancer outcomes, as well as a potential clinical actionability as a biomarker.
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Affiliation(s)
- Gabriele Antonarelli
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, 20139 Milan, Italy
- Department of Oncology and Hemato-Oncology (DIPO), University of Milan, 20122 Milan, Italy
| | - Valentina Pieri
- Neural Stem Cell Biology Unit, Division of Neuroscience, IRCCS San Raffaele Hospital, 20132 Milan, Italy
- Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Francesca Maria Porta
- Division of Pathology, European Institute of Oncology (IEO), IRCCS, 20141 Milan, Italy
- School of Pathology, University of Milan, 20122 Milan, Italy
| | - Nicola Fusco
- Department of Oncology and Hemato-Oncology (DIPO), University of Milan, 20122 Milan, Italy
- Division of Pathology, European Institute of Oncology (IEO), IRCCS, 20141 Milan, Italy
| | | | - Giuseppe Curigliano
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, 20139 Milan, Italy
- Department of Oncology and Hemato-Oncology (DIPO), University of Milan, 20122 Milan, Italy
| | - Carmen Criscitiello
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, 20139 Milan, Italy
- Department of Oncology and Hemato-Oncology (DIPO), University of Milan, 20122 Milan, Italy
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15
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Martínez-Bailén M, Rojo J, Ramos-Soriano J. Multivalent glycosystems for human lectins. Chem Soc Rev 2023; 52:536-572. [PMID: 36545903 DOI: 10.1039/d2cs00736c] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Human lectins are involved in a wide variety of biological processes, both physiological and pathological, which have attracted the interest of the scientific community working in the glycoscience field. Multivalent glycosystems have been employed as useful tools to understand carbohydrate-lectin binding processes as well as for biomedical applications. The review shows the different scaffolds designed for a multivalent presentation of sugars and their corresponding binding studies to lectins and in some cases, their biological activities. We summarise this research by organizing based on lectin types to highlight the progression in this active field. The paper provides an overall picture of how these contributions have furnished relevant information on this topic to help in understanding and participate in these carbohydrate-lectin interactions.
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Affiliation(s)
- Macarena Martínez-Bailén
- Glycosystems Laboratory, Instituto de Investigaciones Químicas (IIQ), CSIC - Universidad de Sevilla, Av. Américo Vespucio 49, Seville 41092, Spain.
| | - Javier Rojo
- Glycosystems Laboratory, Instituto de Investigaciones Químicas (IIQ), CSIC - Universidad de Sevilla, Av. Américo Vespucio 49, Seville 41092, Spain.
| | - Javier Ramos-Soriano
- Glycosystems Laboratory, Instituto de Investigaciones Químicas (IIQ), CSIC - Universidad de Sevilla, Av. Américo Vespucio 49, Seville 41092, Spain.
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16
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A roadmap for translational cancer glycoimmunology at single cell resolution. J Exp Clin Cancer Res 2022; 41:143. [PMID: 35428302 PMCID: PMC9013178 DOI: 10.1186/s13046-022-02335-z] [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: 02/03/2022] [Accepted: 03/17/2022] [Indexed: 11/11/2022] Open
Abstract
Cancer cells can evade immune responses by exploiting inhibitory immune checkpoints. Immune checkpoint inhibitor (ICI) therapies based on anti-CTLA-4 and anti-PD-1/PD-L1 antibodies have been extensively explored over the recent years to unleash otherwise compromised anti-cancer immune responses. However, it is also well established that immune suppression is a multifactorial process involving an intricate crosstalk between cancer cells and the immune systems. The cancer glycome is emerging as a relevant source of immune checkpoints governing immunosuppressive behaviour in immune cells, paving an avenue for novel immunotherapeutic options. This review addresses the current state-of-the-art concerning the role played by glycans controlling innate and adaptive immune responses, while shedding light on available experimental models for glycoimmunology. We also emphasize the tremendous progress observed in the development of humanized models for immunology, the paramount contribution of advances in high-throughput single-cell analysis in this context, and the importance of including predictive machine learning algorithms in translational research. This may constitute an important roadmap for glycoimmunology, supporting careful adoption of models foreseeing clinical translation of fundamental glycobiology knowledge towards next generation immunotherapies.
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17
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Lu H, Wu X, Peng Y, Sun R, Nie Y, Li J, Wang M, Luo Y, Peng L, Fei Y, Zhou J, Zhang W, Zeng X. TSLP promoting B cell proliferation and polarizing follicular helper T cell as a therapeutic target in IgG4-related disease. J Transl Med 2022; 20:414. [PMID: 36076269 PMCID: PMC9461269 DOI: 10.1186/s12967-022-03606-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 08/22/2022] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVE To figure out the functions of thymic stromal lymphopoietin (TSLP) in IgG4-related disease (IgG4-RD). METHODS Plasma TSLP levels were tested by Elisa, and its receptors were detected by flow cytometry. Expressions of TSLP and TSLPR in involved tissues were stained by immunohistochemistry and immunofluorescence. Proliferation, apoptosis, and B subsets of TSLP stimulated-B cells were analyzed by flow cytometry. TSLP-stimulated B cells were co-cultured with CD4+ Naïve T cells. Signaling pathway was identified by RNA-sequencing and western blot. Anti-TSLP therapy was adapted in LatY136F knock-in mice (Lat, IgG4-RD mouse model). RESULTS Plasma TSLP level was increased in IgG4-RD patients and was positively correlated with serum IgG4 level and responder index (RI). TSLPR was co-localized with CD19+ B cells in the submandibular glands (SMGs) of IgG4-RD. TSLP promoted B cell proliferation, and TSLP-activated B cells polarized CD4+ naive T cells into follicular helper T (Tfh) cells through OX40L. RNA-sequencing identified JAK-STAT signaling pathway in TSLP-activated B cells and it was verified by western blot. Anti-TSLP therapy alleviated the inflammation of lung in Lat mice. CONCLUSION Elevated TSLP in IgG4-RD promoted B cells proliferation and polarized Tfh cells and might be served as a potential therapeutic target.
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Affiliation(s)
- Hui Lu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), State Key Laboratory of Complex Severe and Rare Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xunyao Wu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), State Key Laboratory of Complex Severe and Rare Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yu Peng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), State Key Laboratory of Complex Severe and Rare Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Ruijie Sun
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), State Key Laboratory of Complex Severe and Rare Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yuxue Nie
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), State Key Laboratory of Complex Severe and Rare Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jingna Li
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), State Key Laboratory of Complex Severe and Rare Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Mu Wang
- Department of Stomatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yaping Luo
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Linyi Peng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), State Key Laboratory of Complex Severe and Rare Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yunyun Fei
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), State Key Laboratory of Complex Severe and Rare Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jiaxin Zhou
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), State Key Laboratory of Complex Severe and Rare Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
| | - Wen Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), State Key Laboratory of Complex Severe and Rare Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
| | - Xiaofeng Zeng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), State Key Laboratory of Complex Severe and Rare Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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18
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Radovani B, Gudelj I. N-Glycosylation and Inflammation; the Not-So-Sweet Relation. Front Immunol 2022; 13:893365. [PMID: 35833138 PMCID: PMC9272703 DOI: 10.3389/fimmu.2022.893365] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 05/30/2022] [Indexed: 12/28/2022] Open
Abstract
Chronic inflammation is the main feature of many long-term inflammatory diseases such as autoimmune diseases, metabolic disorders, and cancer. There is a growing number of studies in which alterations of N-glycosylation have been observed in many pathophysiological conditions, yet studies of the underlying mechanisms that precede N-glycome changes are still sparse. Proinflammatory cytokines have been shown to alter the substrate synthesis pathways as well as the expression of glycosyltransferases required for the biosynthesis of N-glycans. The resulting N-glycosylation changes can further contribute to disease pathogenesis through modulation of various aspects of immune cell processes, including those relevant to pathogen recognition and fine-tuning the inflammatory response. This review summarizes our current knowledge of inflammation-induced N-glycosylation changes, with a particular focus on specific subsets of immune cells of innate and adaptive immunity and how these changes affect their effector functions, cell interactions, and signal transduction.
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Affiliation(s)
- Barbara Radovani
- Department of Biotechnology, University of Rijeka, Rijeka, Croatia
| | - Ivan Gudelj
- Department of Biotechnology, University of Rijeka, Rijeka, Croatia
- Genos Glycoscience Research Laboratory, Zagreb, Croatia
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19
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Ribeiro F, Perucha E, Graca L. T follicular cells: the regulators of germinal centre homeostasis. Immunol Lett 2022; 244:1-11. [DOI: 10.1016/j.imlet.2022.02.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 02/18/2022] [Accepted: 02/24/2022] [Indexed: 01/05/2023]
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20
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Zou X, Zhang Y, Wang S, Wang X, Yang W, Li Y. Attenuate ICOSL and IL-27 in Aire-overexpressing DC2.4 cells suppress TFH cell differentiation. Immunobiology 2021; 226:152147. [PMID: 34710738 DOI: 10.1016/j.imbio.2021.152147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 09/28/2021] [Accepted: 10/13/2021] [Indexed: 10/20/2022]
Abstract
Autoimmune regulator (Aire) is a transcription factor that plays a pivotal role in the maintenance of immune tolerance. However, little is known about its roles in peripheral immune tolerance. Aire is predominantly expressed in dendritic cells (DCs) in the periphery. DCs with higher inducible costimulatory ligand (ICOSL) expression and interleukin (IL)-27 production have been reported highly suggesting its roles in inducing follicular helper T cells (TFH). Here we use Aire-overexpressing DC2.4 cells in a coculture system composed of naïve CD4+ T cells to test whether Aire in DCs affects TFH cell differentiation. We found that the frequency of TFH cells and its specific cytokine IL-21 were decreased in CD4+ T lymphocytes after cocultured with Aire overexpressed DC2.4 cells. In activated DCs, ICOSL expression and IL-27 production were significantly suppressed by Aire. Furthermore, addition of recombinant ICOSL or IL-27 in the coculture system enhanced TFH cell differentiation and IL-21 expression. These results revealed that Aire plays an indispensable role in the repression of dendritic cells on the differentiation and function of TFH cells by inhibiting ICOSL and IL-27 expression.
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Affiliation(s)
- Xueyang Zou
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
| | - Yi Zhang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
| | - Shuang Wang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China
| | - Xiaoya Wang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China
| | - Wei Yang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
| | - Yi Li
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
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21
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Oliveira YLDC, Oliveira LM, Cirilo TM, Fujiwara RT, Bueno LL, Dolabella SS. T follicular helper cells: Their development and importance in the context of helminthiasis. Clin Immunol 2021; 231:108844. [PMID: 34478881 DOI: 10.1016/j.clim.2021.108844] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 08/25/2021] [Accepted: 08/28/2021] [Indexed: 10/20/2022]
Abstract
The development of T follicular helper cells (Tfh) is a multifactorial process that occurs in multiple stages. After their activation the Tfh cells interact with the B cells to complete their differentiation. During this process, the Tfh cells begin to express canonical molecules such as the transcription factor B-cell lymphoma 6 protein, the CXC chemokine receptors type 5, and the inducible T-cell costimulator, as well as secreting other molecules such as IL-21. This whole process is regulated positively and negatively by several factors so that the best response is offered in the face of diseases of various origins, among them helminthiasis. In this context, the role of circulating Tfh, IL-4 and IgG subtypes is essential for an effective response against these pathogens. In this review, the migration process and the differentiation of Tfh, the regulation, their cell subtypes and the role of Tfh in the context of helminth infections will be addressed.
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Affiliation(s)
| | - Luciana Maria Oliveira
- Departamento de Morfologia, Instituto de Ciências Biológicas e da Saúde, Universidade Federal de Sergipe, São Cristóvão 49100-000, SE, Brazil
| | - Tatyane Martins Cirilo
- Programa de Pós-Graduação em Biologia Parasitária, Universidade Federal de Sergipe, São Cristóvão 49100-000, SE, Brazil
| | - Ricardo Toshio Fujiwara
- Programa de Pós-Graduação em Biologia Parasitária, Universidade Federal de Sergipe, São Cristóvão 49100-000, SE, Brazil; Departamento de Parasitologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, MG, Brazil
| | - Lilian Lacerda Bueno
- Departamento de Parasitologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, MG, Brazil.
| | - Silvio Santana Dolabella
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal de Sergipe, São Cristóvão 49100-000, SE, Brazil; Programa de Pós-Graduação em Biologia Parasitária, Universidade Federal de Sergipe, São Cristóvão 49100-000, SE, Brazil.
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22
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The dual role of IL-27 in CD4+T cells. Mol Immunol 2021; 138:172-180. [PMID: 34438225 DOI: 10.1016/j.molimm.2021.08.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 07/02/2021] [Accepted: 08/01/2021] [Indexed: 12/19/2022]
Abstract
Interleukin-27 (IL-27), a member of the IL-6/IL-12 family, has diverse regulatory functions in various immune responses, and is recognised as a potent agonist and antagonist of CD4+T cells in different contexts. However, this dual role and underlying mechanisms have not been completely defined. In the present review, we summarise the dual role of IL-27 in CD4+T cells. In particular, we aimed to decipher its mechanism to better understand the context-dependent function of IL-27 in CD4+T cells. Furthermore, we propose a possible mechanism for the dual role of IL-27. This may be helpful for the development of appropriate IL-27 treatments in various clinical settings.
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23
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Anderluh M, Berti F, Bzducha‐Wróbel A, Chiodo F, Colombo C, Compostella F, Durlik K, Ferhati X, Holmdahl R, Jovanovic D, Kaca W, Lay L, Marinovic‐Cincovic M, Marradi M, Ozil M, Polito L, Reina‐Martin JJ, Reis CA, Sackstein R, Silipo A, Švajger U, Vaněk O, Yamamoto F, Richichi B, van Vliet SJ. Emerging glyco-based strategies to steer immune responses. FEBS J 2021; 288:4746-4772. [PMID: 33752265 PMCID: PMC8453523 DOI: 10.1111/febs.15830] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 02/12/2021] [Accepted: 03/19/2021] [Indexed: 02/06/2023]
Abstract
Glycan structures are common posttranslational modifications of proteins, which serve multiple important structural roles (for instance in protein folding), but also are crucial participants in cell-cell communications and in the regulation of immune responses. Through the interaction with glycan-binding receptors, glycans are able to affect the activation status of antigen-presenting cells, leading either to induction of pro-inflammatory responses or to suppression of immunity and instigation of immune tolerance. This unique feature of glycans has attracted the interest and spurred collaborations of glyco-chemists and glyco-immunologists to develop glycan-based tools as potential therapeutic approaches in the fight against diseases such as cancer and autoimmune conditions. In this review, we highlight emerging advances in this field, and in particular, we discuss on how glycan-modified conjugates or glycoengineered cells can be employed as targeting devices to direct tumor antigens to lectin receptors on antigen-presenting cells, like dendritic cells. In addition, we address how glycan-based nanoparticles can act as delivery platforms to enhance immune responses. Finally, we discuss some of the latest developments in glycan-based therapies, including chimeric antigen receptor (CAR)-T cells to achieve targeting of tumor-associated glycan-specific epitopes, as well as the use of glycan moieties to suppress ongoing immune responses, especially in the context of autoimmunity.
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Affiliation(s)
- Marko Anderluh
- Chair of Pharmaceutical ChemistryFaculty of PharmacyUniversity of LjubljanaSlovenia
| | | | - Anna Bzducha‐Wróbel
- Department of Biotechnology and Food MicrobiologyWarsaw University of Life Sciences‐SGGWPoland
| | - Fabrizio Chiodo
- Department of Molecular Cell Biology and ImmunologyCancer Center AmsterdamAmsterdam Infection and Immunity InstituteAmsterdam UMCVrije Universiteit AmsterdamNetherlands
| | - Cinzia Colombo
- Department of Chemistry and CRC Materiali Polimerici (LaMPo)University of MilanItaly
| | - Federica Compostella
- Department of Medical Biotechnology and Translational MedicineUniversity of MilanItaly
| | - Katarzyna Durlik
- Department of Microbiology and ParasitologyJan Kochanowski UniversityKielcePoland
| | - Xhenti Ferhati
- Department of Chemistry ‘Ugo Schiff’University of FlorenceFlorenceItaly
| | - Rikard Holmdahl
- Division of Medical Inflammation ResearchDepartment of Medical Biochemistry and BiophysicsKarolinska InstituteStockholmSweden
| | - Dragana Jovanovic
- Vinča Institute of Nuclear Sciences ‐ National Institute of the Republic of SerbiaUniversity of BelgradeSerbia
| | - Wieslaw Kaca
- Department of Microbiology and ParasitologyJan Kochanowski UniversityKielcePoland
| | - Luigi Lay
- Department of Chemistry and CRC Materiali Polimerici (LaMPo)University of MilanItaly
| | - Milena Marinovic‐Cincovic
- Vinča Institute of Nuclear Sciences ‐ National Institute of the Republic of SerbiaUniversity of BelgradeSerbia
| | - Marco Marradi
- Department of Chemistry ‘Ugo Schiff’University of FlorenceFlorenceItaly
| | - Musa Ozil
- Department of ChemistryFaculty of Arts and SciencesRecep Tayyip Erdogan University RizeTurkey
| | | | | | - Celso A. Reis
- I3S – Instituto de Investigação e Inovação em SaúdeUniversidade do PortoPortugal
- IPATIMUP‐Institute of Molecular Pathology and ImmunologyInstituto de Ciências Biomédicas Abel SalazarUniversity of PortoPortugal
| | - Robert Sackstein
- Department of Translational Medicinethe Translational Glycobiology InstituteHerbert Wertheim College of MedicineFlorida International UniversityMiamiFLUSA
| | - Alba Silipo
- Department of Chemical SciencesUniversity of Naples Federico IIComplesso Universitario Monte Sant’AngeloNapoliItaly
| | - Urban Švajger
- Blood Transfusion Center of SloveniaLjubljanaSlovenia
| | - Ondřej Vaněk
- Department of BiochemistryFaculty of ScienceCharles UniversityPragueCzech Republic
| | - Fumiichiro Yamamoto
- Immunohematology & Glycobiology LaboratoryJosep Carreras Leukaemia Research InstituteBadalonaSpain
| | - Barbara Richichi
- Department of Chemistry ‘Ugo Schiff’University of FlorenceFlorenceItaly
| | - Sandra J. van Vliet
- Department of Molecular Cell Biology and ImmunologyCancer Center AmsterdamAmsterdam Infection and Immunity InstituteAmsterdam UMCVrije Universiteit AmsterdamNetherlands
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24
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Naranjo-Lucena A, Correia CN, Molina-Hernández V, Martínez-Moreno Á, Browne JA, Pérez J, MacHugh DE, Mulcahy G. Transcriptomic Analysis of Ovine Hepatic Lymph Node Following Fasciola hepatica Infection - Inhibition of NK Cell and IgE-Mediated Signaling. Front Immunol 2021; 12:687579. [PMID: 34122452 PMCID: PMC8194261 DOI: 10.3389/fimmu.2021.687579] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 05/11/2021] [Indexed: 01/15/2023] Open
Abstract
Fasciola hepatica is a trematode parasite responsible for major economic losses in livestock production, and is also a food-borne zoonotic agent in developing rural regions. For years, the immunoregulatory mechanisms employed by the parasite have hampered efforts to develop a successful vaccine candidate. Given that a comprehensive understanding of the immune response to infection is needed, we investigated the gene expression changes in ovine hepatic lymph nodes after experimental infection with F. hepatica. Lymph nodes from uninfected and infected animals were processed for RNA sequencing (RNA-seq) at 16 weeks post-infection. Comparison of groups revealed 5,132 differentially-expressed genes (DEGs). An inhibition of pro-inflammatory pathways, which has previously been described during fasciolosis, was evident in our data. However, other signals previously identified in ruminant peripheral blood mononuclear cells (PBMC) or liver tissue, such as activation of TGF-β or apoptosis-related pathways were not detected. We found inhibition of some key immunological pathways, including natural killer (NK) cell activity and IgE-mediated signaling. These may point to additional some as yet unrecognized mechanisms employed by the parasite to evade the host immune response. Understanding these, and leveraging information from this and other omics studies, will be important for the development of future vaccine prototypes against this parasite.
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Affiliation(s)
| | - Carolina N Correia
- Animal Genomics Laboratory, UCD School of Agriculture and Food Science, Dublin, Ireland
| | - Verónica Molina-Hernández
- Departamento de Anatomía y Anatomía Patológica Comparadas y Toxicología, Facultad de Veterinaria, Universidad de Córdoba, Córdoba, Spain
| | - Álvaro Martínez-Moreno
- Departamento de Sanidad Animal (Parasitología), Facultad de Veterinaria, Universidad de Córdoba, Córdoba, Spain
| | - John A Browne
- Animal Genomics Laboratory, UCD School of Agriculture and Food Science, Dublin, Ireland
| | - José Pérez
- Departamento de Anatomía y Anatomía Patológica Comparadas y Toxicología, Facultad de Veterinaria, Universidad de Córdoba, Córdoba, Spain
| | - David E MacHugh
- Animal Genomics Laboratory, UCD School of Agriculture and Food Science, Dublin, Ireland.,UCD Conway Institute of Biomolecular and Biomedical Research, Dublin, Ireland
| | - Grace Mulcahy
- UCD School of Veterinary Medicine, Dublin, Ireland.,UCD Conway Institute of Biomolecular and Biomedical Research, Dublin, Ireland
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25
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Reens AL, Cabral DJ, Liang X, Norton JE, Therien AG, Hazuda DJ, Swaminathan G. Immunomodulation by the Commensal Microbiome During Immune-Targeted Interventions: Focus on Cancer Immune Checkpoint Inhibitor Therapy and Vaccination. Front Immunol 2021; 12:643255. [PMID: 34054810 PMCID: PMC8155485 DOI: 10.3389/fimmu.2021.643255] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 04/22/2021] [Indexed: 12/11/2022] Open
Abstract
Emerging evidence in clinical and preclinical studies indicates that success of immunotherapies can be impacted by the state of the microbiome. Understanding the role of the microbiome during immune-targeted interventions could help us understand heterogeneity of treatment success, predict outcomes, and develop additional strategies to improve efficacy. In this review, we discuss key studies that reveal reciprocal interactions between the microbiome, the immune system, and the outcome of immune interventions. We focus on cancer immune checkpoint inhibitor treatment and vaccination as two crucial therapeutic areas with strong potential for immunomodulation by the microbiota. By juxtaposing studies across both therapeutic areas, we highlight three factors prominently involved in microbial immunomodulation: short-chain fatty acids, microbe-associate molecular patterns (MAMPs), and inflammatory cytokines. Continued interrogation of these models and pathways may reveal critical mechanistic synergies between the microbiome and the immune system, resulting in novel approaches designed to influence the efficacy of immune-targeted interventions.
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Affiliation(s)
- Abigail L. Reens
- Exploratory Science Center, Merck & Co., Inc., Cambridge, MA, United States
| | - Damien J. Cabral
- Exploratory Science Center, Merck & Co., Inc., Cambridge, MA, United States
| | - Xue Liang
- Exploratory Science Center, Merck & Co., Inc., Cambridge, MA, United States
| | - James E. Norton
- Exploratory Science Center, Merck & Co., Inc., Cambridge, MA, United States
| | - Alex G. Therien
- Exploratory Science Center, Merck & Co., Inc., Cambridge, MA, United States
| | - Daria J. Hazuda
- Exploratory Science Center, Merck & Co., Inc., Cambridge, MA, United States
- Infectious Disease and Vaccine Research, Merck & Co., Inc., West Point, PA, United States
| | - Gokul Swaminathan
- Exploratory Science Center, Merck & Co., Inc., Cambridge, MA, United States
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26
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Chan HC, Wang SC, Lin CH, Lin YZ, Li RN, Yen JH. A novel CD209 polymorphism is associated with rheumatoid arthritis patients in Taiwan. J Clin Lab Anal 2021; 35:e23751. [PMID: 33792986 PMCID: PMC8128313 DOI: 10.1002/jcla.23751] [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: 08/11/2020] [Revised: 01/29/2021] [Accepted: 02/17/2021] [Indexed: 11/30/2022] Open
Abstract
Single nucleotide polymorphisms (SNPs) in the promoter region of CD209 (cluster of differentiation 209) may influence expression levels, and higher expression of CD209 on immune cells correlate with severity of cartilage destruction in patients with rheumatoid arthritis (RA). Due to the lack of a comprehensive study, this study aimed to investigate the CD209 promoter variants and haplotypes in a Taiwanese population and the association with RA development. Deoxyribonucleic acid (DNA) of peripheral blood mononuclear cells from 126 RA patients and 124 healthy controls was purified, and the CD209 gene promoter was amplified by polymerase chain reaction and analyzed by Sanger sequencing. Results showed that a novel variant −96C>A polymorphism in CD209 promoter was identified in the Taiwanese population, and the frequency was significantly higher in RA patients than in controls (11.51% vs. 2.42%, P < .0001). The odds ratio (OR) for the development of RA was 5.88 (95% CI 2.35–14.74, P < .0001). Other known variants were also evaluated; for instance, −1180 T/T (rs7359874) was increased in RA patients, and the OR for the development of RA was 3.26, 95% CI 0.85–12.52, P = .07). Besides, the haplotype frequencies were calculated; −1180A‐939C‐871 T‐336 T‐139 T‐96A and −1180 T‐939 T‐871C‐336 T‐139C‐96A were increased in RA patients (P = .004 and 0.05, respectively). In summary, CD209‐96A variant could be an important factor for the development of RA in the Taiwanese population.
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Affiliation(s)
- Hua-Chen Chan
- Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung City, Taiwan
| | - Shu-Chen Wang
- Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung City, Taiwan
| | - Chia-Hui Lin
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung City, Taiwan
| | - Yuan-Zhao Lin
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung City, Taiwan
| | - Ruei-Nian Li
- Department of Biomedical Science and Environmental Biology, College of Life Science, Kaohsiung Medical University, Kaohsiung City, Taiwan
| | - Jeng-Hsien Yen
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung City, Taiwan.,Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung City, Taiwan.,Department of Biological Science and Technology, National Chiao Tung University, Hsinchu City, Taiwan.,Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan
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27
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The role of O-glycosylation in human disease. Mol Aspects Med 2021; 79:100964. [PMID: 33775405 DOI: 10.1016/j.mam.2021.100964] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 03/10/2021] [Indexed: 02/06/2023]
Abstract
O-glycosylation is a highly frequent post-translation modification of proteins, with important functional implications in both physiological and disease contexts. The biosynthesis of O-glycans depends on several layers of regulation of the cellular glycosylation machinery, being organ-, tissue- and cell-specific. This review provides insights on the molecular mechanism underlying O-glycan biosynthesis and modification, and highlights illustrative examples of diseases that are triggered or modulated by aberrant cellular O-glycosylation. Particular relevance is given to genetic disorders of glycosylation, infectious diseases and cancer. Finally, we address the potential of O-glycans and their biosynthetic pathways as targets for novel therapeutic strategies.
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28
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Cao Y, Dong L, He Y, Hu X, Hou Y, Dong Y, Yang Q, Bi Y, Liu G. The direct and indirect regulation of follicular T helper cell differentiation in inflammation and cancer. J Cell Physiol 2021; 236:5466-5480. [PMID: 33421124 DOI: 10.1002/jcp.30263] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 12/03/2020] [Accepted: 12/24/2020] [Indexed: 12/12/2022]
Abstract
Follicular T helper (Tfh) cells play important roles in facilitating B-cell differentiation and inducing the antibody response in humoral immunity and immune-associated inflammatory diseases, including infections, autoimmune diseases, and cancers. However, Tfh cell differentiation is mainly achieved through self-directed differentiation regulation and the indirect regulation mechanism of antigen-presenting cells (APCs). During the direct intrinsic differentiation of naïve CD4+ T cells into Tfh cells, Bcl-6, as the characteristic transcription factor, plays the core role of transcriptional regulation. APCs indirectly drive Tfh cell differentiation mainly by changing cytokine secretion mechanisms. Altered metabolic signaling is also critically involved in Tfh cell differentiation. This review summarizes the recent progress in understanding the direct and indirect regulatory signals and metabolic mechanisms of Tfh cell differentiation and function in immune-associated diseases.
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Affiliation(s)
- Yejin Cao
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, No. 19, Xinjiekouwai Street, Haidian District, Beijing, China
| | - Lin Dong
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, No. 19, Xinjiekouwai Street, Haidian District, Beijing, China
| | - Ying He
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, No. 19, Xinjiekouwai Street, Haidian District, Beijing, China
| | - Xuelian Hu
- Immunochina Pharmaceuticals Co., Ltd., No. 80, Xingshikou Road, Haidian District, Beijing, China
| | - Yueru Hou
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, No. 19, Xinjiekouwai Street, Haidian District, Beijing, China
| | - Yingjie Dong
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, No. 19, Xinjiekouwai Street, Haidian District, Beijing, China
| | - Qiuli Yang
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, No. 19, Xinjiekouwai Street, Haidian District, Beijing, China
| | - Yujing Bi
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, No. 20, East Street, Fengtai District, Beijing, China
| | - Guangwei Liu
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, No. 19, Xinjiekouwai Street, Haidian District, Beijing, China
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DC-SIGN signalling induced by Trichinella spiralis products contributes to the tolerogenic signatures of human dendritic cells. Sci Rep 2020; 10:20283. [PMID: 33219293 PMCID: PMC7679451 DOI: 10.1038/s41598-020-77497-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 11/11/2020] [Indexed: 12/28/2022] Open
Abstract
Tolerogenic dendritic cells (tolDCs) are central players in the maintenance of immune tolerance and thereby have been identified as the most favourable candidates for cell therapy of autoimmune diseases. We have recently shown that excretory-secretory products (ES L1) released by Trichinella spiralis larvae induce stable human tolDCs in vitro via Toll-like receptor 2 (TLR2) and TLR4. However, engagement of these receptors did not fully explain the tolerogenic profile of DCs. Here, we observed for the first time that dendritic cell-specific ICAM-3 grabbing non-integrin (DC-SIGN) interacts with highly glycosylated ES L1 and contributes to the generation of ES L1-induced tolDCs. Blocking DC-SIGN interfered with the ES L1-induced higher expression of CD40 and CCR7 and the production of IL-10 and TGF-β by DCs. The cooperation of TLR2, TLR4 and DC-SIGN receptors is of importance for the capacity of DCs to prime T cell response toward Th2 and to induce expansion of CD4+CD25+Foxp3+ T cells, as well as for the production of IL-10 and TGF-β by these cells. Overall, these results indicate that induction of tolDCs by ES L1 involves engagement of multiple pattern recognition receptors namely, TLR2, TLR4 and DC-SIGN.
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30
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Beizavi Z, Zohouri M, Asadipour M, Ghaderi A. IL-27, a pleiotropic cytokine for fine-tuning the immune response in cancer. Int Rev Immunol 2020; 40:319-329. [PMID: 33146571 DOI: 10.1080/08830185.2020.1840565] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 09/23/2020] [Accepted: 10/06/2020] [Indexed: 12/25/2022]
Abstract
Interleukin (IL)-27, a member of the IL-6/IL-12 family, has an important role in modulating inflammation in partnership with innate and adaptive immune cells. IL-27 binding to IL-27R starts downstream signaling based on the target cells. It can instigate inflammation by inducing CD4+ T cell proliferation, Th1 polarization, cytotoxic T cell activation, generation of the natural killer cell, and macrophage and dendritic cell activation. However, by inducing programmed cell death and suppression of effector cells, IL-27 can suppress inflammation and return the immune response to hemostasis. Altogether, IL-27 displays multifaceted dual functions, which may result in either pro- or anti-inflammatory effects. Recent investigations indicated the antitumor activity of IL-27 via inducing Th1, and CTL responses and generating NK cells. On the other hand, IL-27 also can promote tumor cells' proliferation, survival, and angiogenesis. In the present review, we'll discuss recent advances concerning the role of IL-27 in inflammatory diseases such as infections, autoimmune diseases with a focus on cancer.
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Affiliation(s)
- Zahra Beizavi
- Department of Surgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahshid Zohouri
- Shiraz Institute for Cancer Research, School of medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Morvarid Asadipour
- Shiraz Institute for Cancer Research, School of medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abbas Ghaderi
- Shiraz Institute for Cancer Research, School of medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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31
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Valverde P, Martínez JD, Cañada FJ, Ardá A, Jiménez-Barbero J. Molecular Recognition in C-Type Lectins: The Cases of DC-SIGN, Langerin, MGL, and L-Sectin. Chembiochem 2020; 21:2999-3025. [PMID: 32426893 PMCID: PMC7276794 DOI: 10.1002/cbic.202000238] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 05/19/2020] [Indexed: 12/16/2022]
Abstract
Carbohydrates play a pivotal role in intercellular communication processes. In particular, glycan antigens are key for sustaining homeostasis, helping leukocytes to distinguish damaged tissues and invading pathogens from healthy tissues. From a structural perspective, this cross-talk is fairly complex, and multiple membrane proteins guide these recognition processes, including lectins and Toll-like receptors. Since the beginning of this century, lectins have become potential targets for therapeutics for controlling and/or avoiding the progression of pathologies derived from an incorrect immune outcome, including infectious processes, cancer, or autoimmune diseases. Therefore, a detailed knowledge of these receptors is mandatory for the development of specific treatments. In this review, we summarize the current knowledge about four key C-type lectins whose importance has been steadily growing in recent years, focusing in particular on how glycan recognition takes place at the molecular level, but also looking at recent progresses in the quest for therapeutics.
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Affiliation(s)
- Pablo Valverde
- CIC bioGUNE, Basque Research Technology Alliance, BRTA, Bizkaia Technology park, Building 800, 48160, Derio, Spain
| | - J Daniel Martínez
- CIC bioGUNE, Basque Research Technology Alliance, BRTA, Bizkaia Technology park, Building 800, 48160, Derio, Spain
| | - F Javier Cañada
- Centro de Investigaciones Biológicas Margarita Salas, CSIC, Ramiro de Maeztu 9, 28040, Madrid, Spain
- CIBER de Enfermedades Respiratorias (CIBERES), Avda Monforte de Lemos 3-5, 28029, Madrid, Spain
| | - Ana Ardá
- CIC bioGUNE, Basque Research Technology Alliance, BRTA, Bizkaia Technology park, Building 800, 48160, Derio, Spain
| | - Jesús Jiménez-Barbero
- CIC bioGUNE, Basque Research Technology Alliance, BRTA, Bizkaia Technology park, Building 800, 48160, Derio, Spain
- Ikerbasque, Basque Foundation for Science, 48009, Bilbao, Spain
- Department of Organic Chemistry II, Faculty of Science and Technology, UPV-EHU, 48940, Leioa, Spain
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32
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Wang Y, Xiang Y, Xin VW, Wang XW, Peng XC, Liu XQ, Wang D, Li N, Cheng JT, Lyv YN, Cui SZ, Ma Z, Zhang Q, Xin HW. Dendritic cell biology and its role in tumor immunotherapy. J Hematol Oncol 2020; 13:107. [PMID: 32746880 PMCID: PMC7397618 DOI: 10.1186/s13045-020-00939-6] [Citation(s) in RCA: 282] [Impact Index Per Article: 56.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Accepted: 07/20/2020] [Indexed: 12/11/2022] Open
Abstract
As crucial antigen presenting cells, dendritic cells (DCs) play a vital role in tumor immunotherapy. Taking into account the many recent advances in DC biology, we discuss how DCs (1) recognize pathogenic antigens with pattern recognition receptors through specific phagocytosis and through non-specific micropinocytosis, (2) process antigens into small peptides with proper sizes and sequences, and (3) present MHC-peptides to CD4+ and CD8+ T cells to initiate immune responses against invading microbes and aberrant host cells. During anti-tumor immune responses, DC-derived exosomes were discovered to participate in antigen presentation. T cell microvillar dynamics and TCR conformational changes were demonstrated upon DC antigen presentation. Caspase-11-driven hyperactive DCs were recently reported to convert effectors into memory T cells. DCs were also reported to crosstalk with NK cells. Additionally, DCs are the most important sentinel cells for immune surveillance in the tumor microenvironment. Alongside DC biology, we review the latest developments for DC-based tumor immunotherapy in preclinical studies and clinical trials. Personalized DC vaccine-induced T cell immunity, which targets tumor-specific antigens, has been demonstrated to be a promising form of tumor immunotherapy in patients with melanoma. Importantly, allogeneic-IgG-loaded and HLA-restricted neoantigen DC vaccines were discovered to have robust anti-tumor effects in mice. Our comprehensive review of DC biology and its role in tumor immunotherapy aids in the understanding of DCs as the mentors of T cells and as novel tumor immunotherapy cells with immense potential.
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Affiliation(s)
- Yingying Wang
- State Key Laboratory of Respiratory Disease, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095 China
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Faculty of Medicine, Yangtze University, 1 Nanhuan Road, Jingzhou, 434023 Hubei China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Faculty of Medicine, Yangtze University, Jingzhou, 434023 Hubei China
- Department of Gynaecology, Comprehensive Cancer Center, Hannover Medical School, 30625 Hannover, Germany
| | - Ying Xiang
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Faculty of Medicine, Yangtze University, 1 Nanhuan Road, Jingzhou, 434023 Hubei China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Faculty of Medicine, Yangtze University, Jingzhou, 434023 Hubei China
| | | | - Xian-Wang Wang
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Faculty of Medicine, Yangtze University, 1 Nanhuan Road, Jingzhou, 434023 Hubei China
- Department of Laboratory Medicine, School of Basic Medicine, Faculty of Medicine, Yangtze University, 1 Nanhuan Road, Jingzhou, 434023 Hubei China
| | - Xiao-Chun Peng
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Faculty of Medicine, Yangtze University, 1 Nanhuan Road, Jingzhou, 434023 Hubei China
- Department of Pathophysiology, School of Basic Medicine, Faculty of Medicine, Yangtze University, Jingzhou, 434023 Hubei China
| | - Xiao-Qin Liu
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Faculty of Medicine, Yangtze University, 1 Nanhuan Road, Jingzhou, 434023 Hubei China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Faculty of Medicine, Yangtze University, Jingzhou, 434023 Hubei China
- Department of Medical Imaging, School of Basic Medicine, Faculty of Medicine, Yangtze University, Jingzhou, 434023 Hubei China
| | - Dong Wang
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Faculty of Medicine, Yangtze University, 1 Nanhuan Road, Jingzhou, 434023 Hubei China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Faculty of Medicine, Yangtze University, Jingzhou, 434023 Hubei China
| | - Na Li
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, Hubei China
| | - Jun-Ting Cheng
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Faculty of Medicine, Yangtze University, 1 Nanhuan Road, Jingzhou, 434023 Hubei China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Faculty of Medicine, Yangtze University, Jingzhou, 434023 Hubei China
| | - Yan-Ning Lyv
- Institute for Infectious Diseases and Endemic Diseases Prevention and Control, Beijing Center for Diseases Prevention and Control, Beijing, 100013 China
| | - Shu-Zhong Cui
- State Key Laboratory of Respiratory Disease, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095 China
| | - Zhaowu Ma
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Faculty of Medicine, Yangtze University, 1 Nanhuan Road, Jingzhou, 434023 Hubei China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Faculty of Medicine, Yangtze University, Jingzhou, 434023 Hubei China
| | - Qing Zhang
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275 China
- Institute of Sun Yat-sen University in Shenzhen, Shenzhen, China
| | - Hong-Wu Xin
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Faculty of Medicine, Yangtze University, 1 Nanhuan Road, Jingzhou, 434023 Hubei China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Faculty of Medicine, Yangtze University, Jingzhou, 434023 Hubei China
- People’s Hospital of Lianjiang, Lianjiang, 524400 Guangdong China
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33
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Schetters STT, Kruijssen LJW, Crommentuijn MHW, Kalay H, den Haan JMM, van Kooyk Y. Immunological dynamics after subcutaneous immunization with a squalene-based oil-in-water adjuvant. FASEB J 2020; 34:12406-12418. [PMID: 33411367 PMCID: PMC7496326 DOI: 10.1096/fj.202000848r] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 06/24/2020] [Accepted: 07/06/2020] [Indexed: 12/25/2022]
Abstract
The clinically successful adjuvant MF59 is used in seasonal influenza vaccines, which is proposed to enhance immunity by creating an immune-competent microenvironment in the muscle that allows recruitment of immune cells that drive adaptive immune responses. Here, we examined whether the clinically successful adjuvants MF59/AddaVax could be used for subcutaneous use and how antigen delivery can be synergized with cellular dynamics at the vaccination site. Subcutaneous injection of AddaVax leads to thickening of the skin, characterized by a neutrophil-monocyte recruitment sequence. Skin-infiltrating CCR2+Ly6Chigh monocytes showed differentiation to CD11b+Ly6C+MHCII+CD11c+CD64+ monocyte-derived DCs over time in the hypodermal layers of the skin, expressing high levels of CD209a/mDC-SIGN. Surprisingly, skin thickening was accompanied with increased white adipose tissue highly enriched with monocytes. Analysis of the skin-draining lymph nodes revealed early increases in neutrophils and moDCs at 12 hours after injection and later increases in migratory cDC2s. Subcutaneous vaccination with AddaVax enhanced antigen-specific CD8+ and CD4+ T cell responses, while moDC targeting using antigen-coupled CD209a antibody additionally boosted humoral responses. Hence, oil-in-water emulsions provide an attractive immune modulatory adjuvants aimed at increasing cellular responses, as well as antibody responses when combined with moDC targeting.
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Affiliation(s)
- Sjoerd T T Schetters
- Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center, Amsterdam, the Netherlands.,Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, VU University, Amsterdam, the Netherlands
| | - Laura J W Kruijssen
- Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center, Amsterdam, the Netherlands.,Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, VU University, Amsterdam, the Netherlands
| | - Matheus H W Crommentuijn
- Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center, Amsterdam, the Netherlands.,Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, VU University, Amsterdam, the Netherlands
| | - Hakan Kalay
- Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center, Amsterdam, the Netherlands.,Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, VU University, Amsterdam, the Netherlands
| | - Joke M M den Haan
- Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center, Amsterdam, the Netherlands.,Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, VU University, Amsterdam, the Netherlands
| | - Yvette van Kooyk
- Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center, Amsterdam, the Netherlands.,Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, VU University, Amsterdam, the Netherlands
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34
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Glycopeptide epitope facilitates HIV-1 envelope specific humoral immune responses by eliciting T cell help. Nat Commun 2020; 11:2550. [PMID: 32439962 PMCID: PMC7242320 DOI: 10.1038/s41467-020-16319-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Accepted: 04/22/2020] [Indexed: 12/25/2022] Open
Abstract
The inherent molecular complexity of human pathogens requires that mammals evolved an adaptive immune system equipped to handle presentation of non-conventional MHC ligands derived from disease-causing agents, such as HIV-1 envelope (Env) glycoprotein. Here, we report that a CD4+ T cell repertoire recognizes a glycopeptide epitope on gp120 presented by MHCII pathway. This glycopeptide is strongly immunogenic in eliciting glycan-dependent cellular and humoral immune responses. The glycopeptide specific CD4+ T cells display a prominent feature of Th2 and Th17 differentiation and exert high efficacy and potency to help Env trimer humoral immune responses. Glycopeptide-induced CD4+ T cell response prior to Env trimer immunization elicits neutralizing antibody development and production of antibodies facilitating uptake of immunogens by antigen-presenting cells. Our identification of gp120 glycopeptide–induced, T cell–specific immune responses offers a foundation for developing future knowledge-based vaccines that elicit strong and long-lasting protective immune responses against HIV-1 infection. T cells recognize peptide antigens presented in the context of MHC but can additionally recognize non-conventional ligands. Here the authors show T cells specific for a HIV-1 associated glycopeptide antigen presented by MHC class II help envelope (Env) trimer induced humoral immune responses.
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35
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Stebegg M, Bignon A, Hill DL, Silva-Cayetano A, Krueger C, Vanderleyden I, Innocentin S, Boon L, Wang J, Zand MS, Dooley J, Clark J, Liston A, Carr E, Linterman MA. Rejuvenating conventional dendritic cells and T follicular helper cell formation after vaccination. eLife 2020; 9:52473. [PMID: 32204792 PMCID: PMC7093110 DOI: 10.7554/elife.52473] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 03/12/2020] [Indexed: 12/22/2022] Open
Abstract
Germinal centres (GCs) are T follicular helper cell (Tfh)-dependent structures that form in response to vaccination, producing long-lived antibody secreting plasma cells and memory B cells that protect against subsequent infection. With advancing age the GC and Tfh cell response declines, resulting in impaired humoral immunity. We sought to discover what underpins the poor Tfh cell response in ageing and whether it is possible to correct it. Here, we demonstrate that older people and aged mice have impaired Tfh cell differentiation upon vaccination. This deficit is preceded by poor activation of conventional dendritic cells type 2 (cDC2) due to reduced type 1 interferon signalling. Importantly, the Tfh and cDC2 cell response can be boosted in aged mice by treatment with a TLR7 agonist. This demonstrates that age-associated defects in the cDC2 and Tfh cell response are not irreversible and can be enhanced to improve vaccine responses in older individuals.
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Affiliation(s)
- Marisa Stebegg
- Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom
| | - Alexandre Bignon
- Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom
| | - Danika Lea Hill
- Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom
| | - Alyssa Silva-Cayetano
- Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom
| | - Christel Krueger
- Epigenetics Programme, Babraham Institute, Cambridge, United Kingdom
| | - Ine Vanderleyden
- Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom
| | - Silvia Innocentin
- Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom
| | | | - Jiong Wang
- Division of Nephrology, Department of Medicine and Clinical and Translational Science Institute, University of Rochester Medical Center, Rochester, United States
| | - Martin S Zand
- Division of Nephrology, Department of Medicine and Clinical and Translational Science Institute, University of Rochester Medical Center, Rochester, United States
| | - James Dooley
- Autoimmune Genetics Laboratory, VIB and University of Leuven, Leuven, Belgium
| | - Jonathan Clark
- Biological Chemistry, Babraham Institute, Cambridge, United Kingdom
| | - Adrian Liston
- Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom
| | - Edward Carr
- Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom.,Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Michelle A Linterman
- Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom
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36
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Stunnenberg M, Sprokholt JK, van Hamme JL, Kaptein TM, Zijlstra-Willems EM, Gringhuis SI, Geijtenbeek TBH. Synthetic Abortive HIV-1 RNAs Induce Potent Antiviral Immunity. Front Immunol 2020; 11:8. [PMID: 32038656 PMCID: PMC6990453 DOI: 10.3389/fimmu.2020.00008] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 01/06/2020] [Indexed: 12/12/2022] Open
Abstract
Strong innate and adaptive immune responses are paramount in combating viral infections. Dendritic cells (DCs) detect viral infections via cytosolic RIG-I like receptors (RLRs) RIG-I and MDA5 leading to MAVS-induced immunity. The DEAD-box RNA helicase DDX3 senses abortive human immunodeficiency virus 1 (HIV-1) transcripts and induces MAVS-dependent type I interferon (IFN) responses, suggesting that abortive HIV-1 RNA transcripts induce antiviral immunity. Little is known about the induction of antiviral immunity by DDX3-ligand abortive HIV-1 RNA. Here we synthesized a 58 nucleotide-long capped RNA (HIV-1 Cap-RNA58) that mimics abortive HIV-1 RNA transcripts. HIV-1 Cap-RNA58 induced potent type I IFN responses in monocyte-derived DCs, monocytes, macrophages and primary CD1c+ DCs. Compared with RLR agonist poly-I:C, HIV-1 Cap-RNA58 induced comparable levels of type I IFN responses, identifying HIV-1 Cap-RNA58 as a potent trigger of antiviral immunity. In monocyte-derived DCs, HIV-1 Cap-RNA58 activated the transcription factors IRF3 and NF-κB. Moreover, HIV-1 Cap-RNA58 induced DC maturation and the expression of pro-inflammatory cytokines. HIV-1 Cap-RNA58-stimulated DCs induced proliferation of CD4+ and CD8+ T cells and differentiated naïve T helper (TH) cells toward a TH2 phenotype. Importantly, treatment of DCs with HIV-1 Cap-RNA58 resulted in an efficient antiviral innate immune response that reduced ongoing HIV-1 replication in DCs. Our data strongly suggest that HIV-1 Cap-RNA58 induces potent innate and adaptive immune responses, making it an interesting addition in vaccine design strategies.
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Affiliation(s)
- Melissa Stunnenberg
- Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Joris K Sprokholt
- Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - John L van Hamme
- Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Tanja M Kaptein
- Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Esther M Zijlstra-Willems
- Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Sonja I Gringhuis
- Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Teunis B H Geijtenbeek
- Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
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37
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Solaymani-Mohammadi S, Eckmann L, Singer SM. Interleukin (IL)-21 in Inflammation and Immunity During Parasitic Diseases. Front Cell Infect Microbiol 2019; 9:401. [PMID: 31867283 PMCID: PMC6904299 DOI: 10.3389/fcimb.2019.00401] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 11/11/2019] [Indexed: 12/30/2022] Open
Abstract
Parasitic diseases cause significant morbidity and mortality in the developing and underdeveloped countries. No efficacious vaccines are available against most parasitic diseases and there is a critical need for developing novel vaccine strategies for care. IL-21 is a pleiotropic cytokine whose functions in protection and immunopathology during parasitic diseases have been explored in limited ways. IL-21 and its cognate receptor, IL-21R, are highly expressed in parasitized organs of infected humans as well in murine models of the human parasitic diseases. Prior studies have indicated the ability of the IL-21/IL-21R signaling axis to regulate the effector functions (e.g., cytokine production) of T cell subsets by enhancing the expression of T-bet and STAT4 in human T cells, resulting in an augmented production of IFN-γ. Mice deficient for either IL-21 (Il21−/−) or IL-21R (Il21r−/−) showed significantly reduced inflammatory responses following parasitic infections as compared with their WT counterparts. Targeting the IL-21/IL-21R signaling axis may provide a novel approach for the development of new therapeutic agents for the prevention of parasite-induced immunopathology and tissue destruction.
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Affiliation(s)
- Shahram Solaymani-Mohammadi
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, United States
| | - Lars Eckmann
- Department of Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Steven M Singer
- Department of Biology, Georgetown University, Washington, DC, United States
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38
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Jan M, Upadhyay C, Hioe CE. HIV-1 Envelope Glycan Composition as a Key Determinant of Efficient Virus Transmission via DC-SIGN and Resistance to Inhibitory Lectins. iScience 2019; 21:413-427. [PMID: 31704652 PMCID: PMC6889591 DOI: 10.1016/j.isci.2019.10.030] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Revised: 09/17/2019] [Accepted: 10/15/2019] [Indexed: 02/04/2023] Open
Abstract
The HIV-1 envelope (Env) surface is shrouded with an assortment of oligomannose-, hybrid-, and complex-type glycans that enable virus interaction with carbohydrate-recognizing lectins. This study examined the importance of glycan heterogeneity for HIV-1 transmission through the trans-infection pathway by the host mannose-binding lectin DC-SIGN. A diversity of glycan content was observed among HIV-1 strains and associated with varying degrees of trans-infection via DC-SIGN and sensitivity to trans-infection blockage by antiviral lectins. When Env glycans were modified to display only the oligomannose type, DC-SIGN-mediated virus capture was enhanced; however, virus trans-infection was diminished because of increased degradation, which was alleviated by incorporation with hybrid-type glycans. Amino acid changes in the Env signal peptide (SP) modulated the Env glycan content, leading to alterations in DC-SIGN-dependent trans-infection and virus sensitivity to antiviral lectins. Hence, SP variation and glycosylation that confer varied types of oligosaccharides to HIV-1 Env are critical determinants for virus fitness and phenotypic diversity.
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Affiliation(s)
- Muzafar Jan
- Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Chitra Upadhyay
- Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA,Research Service, James J. Peters VA Medical Center, Bronx, NY 10468, USA
| | - Catarina E. Hioe
- Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA,Research Service, James J. Peters VA Medical Center, Bronx, NY 10468, USA,Corresponding author
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Peixoto A, Relvas-Santos M, Azevedo R, Santos LL, Ferreira JA. Protein Glycosylation and Tumor Microenvironment Alterations Driving Cancer Hallmarks. Front Oncol 2019; 9:380. [PMID: 31157165 PMCID: PMC6530332 DOI: 10.3389/fonc.2019.00380] [Citation(s) in RCA: 223] [Impact Index Per Article: 37.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Accepted: 04/23/2019] [Indexed: 12/12/2022] Open
Abstract
Decades of research have disclosed a plethora of alterations in protein glycosylation that decisively impact in all stages of disease and ultimately contribute to more aggressive cell phenotypes. The biosynthesis of cancer-associated glycans and its reflection in the glycoproteome is driven by microenvironmental cues and these events act synergistically toward disease evolution. Such intricate crosstalk provides the molecular foundations for the activation of relevant oncogenic pathways and leads to functional alterations driving invasion and disease dissemination. However, it also provides an important source of relevant glyco(neo)epitopes holding tremendous potential for clinical intervention. Therefore, we highlight the transversal nature of glycans throughout the currently accepted cancer hallmarks, with emphasis on the crosstalk between glycans and the tumor microenvironment stromal components. Focus is also set on the pressing need to include glycans and glycoconjugates in comprehensive panomics models envisaging molecular-based precision medicine capable of improving patient care. We foresee that this may provide the necessary rationale for more comprehensive studies and molecular-based intervention.
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Affiliation(s)
- Andreia Peixoto
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal.,Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal.,Tumour and Microenvironment Interactions Group, INEB-Institute for Biomedical Engineering, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Marta Relvas-Santos
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal
| | - Rita Azevedo
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal.,Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal
| | - Lúcio Lara Santos
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal.,Department of Surgical Oncology, Portuguese Institute of Oncology, Porto, Portugal
| | - José Alexandre Ferreira
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal.,Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal.,Porto Comprehensive Cancer Center, Porto, Portugal
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40
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Mucosal T follicular helper cells in SIV-infected rhesus macaques: contributing role of IL-27. Mucosal Immunol 2019; 12:1038-1054. [PMID: 31114010 PMCID: PMC7746526 DOI: 10.1038/s41385-019-0174-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 04/04/2019] [Accepted: 04/17/2019] [Indexed: 02/04/2023]
Abstract
Mesenteric lymph nodes (MLNs), that drain the large and small intestine, are critical sites for the induction of oral tolerance. Although depletion of CD4 T cells in the intestinal lamina propria is a hallmark of HIV infection, CD4 T cell dynamics in MLNs is less known due to the lack of accessibility to these LNs. We demonstrate the early loss of memory CD4 T cells, including T follicular helper cells (Tfh) and a remodeling of MLN architecture in SIV-infected rhesus macaques (RMs). Along with the loss of Tfh cells, we observe the loss of memory B cells and of germinal center B cells. Tfh cells display a Th1 profile with increased levels of the transcription factors that negatively impact on Tfh differentiation and of Stat5 phosphorylation. MLNs of SIV-infected RMs display lower mRNA transcripts encoding for IL-12, IL-23, and IL-35, whereas those coding for IL-27 are not impaired in MLNs. In vitro, IL-27 negatively impacts on Tfh cells and recapitulates the profile observed in SIV-infected RMs. Therefore, early defects of memory CD4 T cells, as well of Tfh cells in MLNs, which play a central role in regulating the mucosal immune response, may have major implications for Aids.
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Pereira MS, Alves I, Vicente M, Campar A, Silva MC, Padrão NA, Pinto V, Fernandes Â, Dias AM, Pinho SS. Glycans as Key Checkpoints of T Cell Activity and Function. Front Immunol 2018; 9:2754. [PMID: 30538706 PMCID: PMC6277680 DOI: 10.3389/fimmu.2018.02754] [Citation(s) in RCA: 110] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 11/08/2018] [Indexed: 12/20/2022] Open
Abstract
The immune system is highly controlled and fine-tuned by glycosylation, through the addition of a diversity of carbohydrates structures (glycans) to virtually all immune cell receptors. Despite a relative backlog in understanding the importance of glycans in the immune system, due to its inherent complexity, remarkable findings have been highlighting the essential contributions of glycosylation in the regulation of both innate and adaptive immune responses with important implications in the pathogenesis of major diseases such as autoimmunity and cancer. Glycans are implicated in fundamental cellular and molecular processes that regulate both stimulatory and inhibitory immune pathways. Besides being actively involved in pathogen recognition through interaction with glycan-binding proteins (such as C-type lectins), glycans have been also shown to regulate key pathophysiological steps within T cell biology such as T cell development and thymocyte selection; T cell activity and signaling as well as T cell differentiation and proliferation. These effects of glycans in T cells functions highlight their importance as determinants of either self-tolerance or T cell hyper-responsiveness which ultimately might be implicated in the creation of tolerogenic pathways in cancer or loss of immunological tolerance in autoimmunity. This review discusses how specific glycans (with a focus on N-linked glycans) act as regulators of T cell biology and their implications in disease.
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Affiliation(s)
- Márcia S Pereira
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) Porto, Portugal.,Institute for Research and Innovation in Health (I3S) Porto, Portugal.,Institute of Biomedical Sciences of Abel Salazar, University of Porto Porto, Portugal
| | - Inês Alves
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) Porto, Portugal.,Institute for Research and Innovation in Health (I3S) Porto, Portugal.,Medical Faculty, University of Porto Porto, Portugal
| | - Manuel Vicente
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) Porto, Portugal.,Institute for Research and Innovation in Health (I3S) Porto, Portugal.,Institute of Biomedical Sciences of Abel Salazar, University of Porto Porto, Portugal
| | - Ana Campar
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) Porto, Portugal.,Institute for Research and Innovation in Health (I3S) Porto, Portugal.,Institute of Biomedical Sciences of Abel Salazar, University of Porto Porto, Portugal.,Centro Hospitalar do Porto Porto, Portugal
| | - Mariana C Silva
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) Porto, Portugal.,Institute for Research and Innovation in Health (I3S) Porto, Portugal
| | - Nuno A Padrão
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) Porto, Portugal.,Institute for Research and Innovation in Health (I3S) Porto, Portugal.,Medical Faculty, University of Porto Porto, Portugal
| | - Vanda Pinto
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) Porto, Portugal.,Institute for Research and Innovation in Health (I3S) Porto, Portugal
| | - Ângela Fernandes
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) Porto, Portugal.,Institute for Research and Innovation in Health (I3S) Porto, Portugal
| | - Ana M Dias
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) Porto, Portugal.,Institute for Research and Innovation in Health (I3S) Porto, Portugal
| | - Salomé S Pinho
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) Porto, Portugal.,Institute for Research and Innovation in Health (I3S) Porto, Portugal.,Medical Faculty, University of Porto Porto, Portugal
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Krishnaswamy JK, Alsén S, Yrlid U, Eisenbarth SC, Williams A. Determination of T Follicular Helper Cell Fate by Dendritic Cells. Front Immunol 2018; 9:2169. [PMID: 30319629 PMCID: PMC6170619 DOI: 10.3389/fimmu.2018.02169] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2018] [Accepted: 09/03/2018] [Indexed: 01/02/2023] Open
Abstract
T follicular helper (Tfh) cells are a specialized subset of CD4+ T cells that collaborate with B cells to promote and regulate humoral responses. Unlike other CD4+ effector lineages, Tfh cells require interactions with both dendritic cells (DCs) and B cells to complete their differentiation. While numerous studies have assessed the potential of different DC subsets to support Tfh priming, the conclusions of these studies depend heavily on the model and method of immunization used. We propose that the location of different DC subsets within the lymph node (LN) and their access to antigen determine their potency in Tfh priming. Finally, we provide a three-step model that accounts for the ability of multiple DC subsets and related lineages to support the Tfh differentiation program.
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Affiliation(s)
| | - Samuel Alsén
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ulf Yrlid
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Stephanie C Eisenbarth
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, United States.,Department of Immunobiology, Yale University School of Medicine, New Haven, CT, United States
| | - Adam Williams
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, United States.,Department of Genetics and Genomic Sciences, University of Connecticut Health Center, Farmington, CT, United States
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44
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Qin L, Waseem TC, Sahoo A, Bieerkehazhi S, Zhou H, Galkina EV, Nurieva R. Insights Into the Molecular Mechanisms of T Follicular Helper-Mediated Immunity and Pathology. Front Immunol 2018; 9:1884. [PMID: 30158933 PMCID: PMC6104131 DOI: 10.3389/fimmu.2018.01884] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 07/31/2018] [Indexed: 12/18/2022] Open
Abstract
T follicular helper (Tfh) cells play key role in providing help to B cells during germinal center (GC) reactions. Generation of protective antibodies against various infections is an important aspect of Tfh-mediated immune responses and the dysregulation of Tfh cell responses has been implicated in various autoimmune disorders, inflammation, and malignancy. Thus, their differentiation and maintenance must be closely regulated to ensure appropriate help to B cells. The generation and function of Tfh cells is regulated by multiple checkpoints including their early priming stage in T zones and throughout the effector stage of differentiation in GCs. Signaling pathways activated downstream of cytokine and costimulatory receptors as well as consequent activation of subset-specific transcriptional factors are essential steps for Tfh cell generation. Thus, understanding the mechanisms underlying Tfh cell-mediated immunity and pathology will bring into spotlight potential targets for novel therapies. In this review, we discuss the recent findings related to the molecular mechanisms of Tfh cell differentiation and their role in normal immune responses and antibody-mediated diseases.
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Affiliation(s)
- Lei Qin
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, United States.,School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Tayab C Waseem
- Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, United States
| | - Anupama Sahoo
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Shayahati Bieerkehazhi
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Hong Zhou
- School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Elena V Galkina
- Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, United States
| | - Roza Nurieva
- Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
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45
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Wu J, Zhang H, Zheng Y, Jin X, Liu M, Li S, Zhao Q, Liu X, Wang Y, Shi M, Zhang S, Tian J, Sun Y, Zhang M, Yu B. The Long Noncoding RNA MALAT1 Induces Tolerogenic Dendritic Cells and Regulatory T Cells via miR155/Dendritic Cell-Specific Intercellular Adhesion Molecule-3 Grabbing Nonintegrin/IL10 Axis. Front Immunol 2018; 9:1847. [PMID: 30150986 PMCID: PMC6099154 DOI: 10.3389/fimmu.2018.01847] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 07/26/2018] [Indexed: 12/21/2022] Open
Abstract
By shaping T cell immunity, tolerogenic dendritic cells (tDCs) play critical roles in the induction of immune tolerance after transplantation. However, the role of long noncoding RNAs (lncRNAs) in the function and immune tolerance of dendritic cells (DCs) is largely unknown. Here, we found that the lncRNA MALAT1 is upregulated in the infiltrating cells of tolerized mice with cardiac allografts and activated DCs. Functionally, MALAT1 overexpression favored a switch in DCs toward a tolerant phenotype. Mechanistically, ectopic MALAT1 promoted dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN) expression by functioning as an miR155 sponge, which is essential for the tolerogenic maintenance of DCs and the DC-SIGN-positive subset with more potent tolerogenic ability. The adoptive transfer of MALAT1-overexpressing DCs promoted cardiac allograft survival and protected from the development of experimental autoimmune myocarditis, accompanied with increasing antigen-specific regulatory T cells. Therefore, overexpressed MALAT1 induces tDCs and immune tolerance in heart transplantation and autoimmune disease by the miRNA-155/DC-SIGH/IL10 axis. This study highlights that the lncRNA MALAT1 is a novel tolerance regulator in immunity that has important implications in settings in which tDCs are preferred.
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Affiliation(s)
- Jian Wu
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China
| | - Hanlu Zhang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China
| | - Yang Zheng
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China
| | - Xiangyuan Jin
- Department of Thoracic Surgery, The Third Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Mingyang Liu
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China
| | - Shuang Li
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China
| | - Qi Zhao
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China
| | - Xianglan Liu
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China
| | - Yongshun Wang
- School of Biomedical Sciences, The University of Hong Kong, Pokfulam, China
| | - Ming Shi
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Shengnan Zhang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China
| | - Jinwei Tian
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China
| | - Yong Sun
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China
| | - Maomao Zhang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China
| | - Bo Yu
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.,The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China
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The Role of Dendritic Cells in the Differentiation of T Follicular Helper Cells. J Immunol Res 2018; 2018:7281453. [PMID: 30057920 PMCID: PMC6051062 DOI: 10.1155/2018/7281453] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Accepted: 06/13/2018] [Indexed: 12/05/2022] Open
Abstract
T follicular helper cells (TFH) are a subset of recently discovered CD4+ T cells. Their major function is to participate in the formation of germinal centres (GCs) and promote B cell proliferation and differentiation to play important roles in the production of antibodies. Currently, the functions of TFH cells are clear. However, the early differentiation of these cells is not clear. Dendritic cells (DCs) participate in the differentiation of TFH cells. Therefore, this article reviewed the research progress regarding the influence of DCs on the differentiation of TFH cells and their major underlying mechanisms.
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Schetters STT, Kruijssen LJW, Crommentuijn MHW, Kalay H, Ochando J, den Haan JMM, Garcia-Vallejo JJ, van Kooyk Y. Mouse DC-SIGN/CD209a as Target for Antigen Delivery and Adaptive Immunity. Front Immunol 2018; 9:990. [PMID: 29867967 PMCID: PMC5949514 DOI: 10.3389/fimmu.2018.00990] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Accepted: 04/20/2018] [Indexed: 12/29/2022] Open
Abstract
The efficacy of vaccination studies aimed at targeting antigens to human DC-SIGN (hDC-SIGN) have been notoriously difficult to study in vivo, as eight dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN) homologs have been described in mice. CD209a/SIGNR5 has been coined as the mouse DC-SIGN (mDC-SIGN) ortholog, based on its expression and location in the genome. Nonetheless, which properties of hDC-SIGN are covered by mDC-SIGN is poorly investigated. One of the most important functions of DC-SIGN is the induction of adaptive immunity. As such, the aim of this study is to determine the capability of mDC-SIGN to induce adaptive immune responses. Here, we show that mDC-SIGN is expressed on GM-CSF cultured bone marrow-derived dendritic cells (BMDCs) and macrophages. However, mDC-SIGN is an internalizing receptor which, unlike hDC-SIGN, quickly resurfaces after internalization. Binding of OVA-coupled anti-mDC-SIGN antibody by BMDCs leads to quick internalization, processing, and presentation to antigen-specific CD8+ and CD4+ T cells, which can be boosted using the TLR4 ligand, monophosphoryl lipid A. In the homeostatic condition, mDC-SIGN is mostly expressed on myeloid cells in the skin and spleen. A subcutaneous injection of fluorescent anti-mDC-SIGN reveals specific targeting to mDC-SIGN+ skin dendritic cells (DCs) and monocyte-derived DCs in situ. A subcutaneous vaccination strategy containing OVA-coupled anti-mDC-SIGN antibody generated antigen-specific polyfunctional CD8+ T cell and CD4+ T cell responses and a strong isotype-switched OVA-specific antibody response in vivo. We conclude that mDC-SIGN shows partly overlapping similarities to hDC-SIGN and that targeting mDC-SIGN provides a valuable approach to investigate the immunological function of DC-SIGN in vivo.
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Affiliation(s)
- Sjoerd T T Schetters
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands
| | - Laura J W Kruijssen
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands
| | - Matheus H W Crommentuijn
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands
| | - Hakan Kalay
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands
| | - Jordi Ochando
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Immunología de Trasplantes, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain
| | - Joke M M den Haan
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands
| | - Juan J Garcia-Vallejo
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands
| | - Yvette van Kooyk
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands
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48
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Li J, Hsu HC, Mountz JD, Allen JG. Unmasking Fucosylation: from Cell Adhesion to Immune System Regulation and Diseases. Cell Chem Biol 2018. [DOI: 10.1016/j.chembiol.2018.02.005] [Citation(s) in RCA: 156] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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49
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Ryu H, Lim H, Choi G, Park YJ, Cho M, Na H, Ahn CW, Kim YC, Kim WU, Lee SH, Chung Y. Atherogenic dyslipidemia promotes autoimmune follicular helper T cell responses via IL-27. Nat Immunol 2018; 19:583-593. [DOI: 10.1038/s41590-018-0102-6] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Accepted: 03/15/2018] [Indexed: 01/01/2023]
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50
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Del Fresno C, Iborra S, Saz-Leal P, Martínez-López M, Sancho D. Flexible Signaling of Myeloid C-Type Lectin Receptors in Immunity and Inflammation. Front Immunol 2018; 9:804. [PMID: 29755458 PMCID: PMC5932189 DOI: 10.3389/fimmu.2018.00804] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 04/03/2018] [Indexed: 12/19/2022] Open
Abstract
Myeloid C-type lectin receptors (CLRs) are important sensors of self and non-self that work in concert with other pattern recognition receptors (PRRs). CLRs have been previously classified based on their signaling motifs as activating or inhibitory receptors. However, specific features of the ligand binding process may result in distinct signaling through a single motif, resulting in the triggering of non-canonical pathways. In addition, CLR ligands are frequently exposed in complex structures that simultaneously bind different CLRs and other PRRs, which lead to integration of heterologous signaling among diverse receptors. Herein, we will review how sensing by myeloid CLRs and crosstalk with heterologous receptors is modulated by many factors affecting their signaling and resulting in differential outcomes for immunity and inflammation. Finding common features among those flexible responses initiated by diverse CLR-ligand partners will help to harness CLR function in immunity and inflammation.
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Affiliation(s)
- Carlos Del Fresno
- Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
| | - Salvador Iborra
- Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.,Department of Immunology, School of Medicine, Universidad Complutense de Madrid, 12 de Octubre Health Research Institute (imas12), Madrid, Spain
| | - Paula Saz-Leal
- Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
| | - María Martínez-López
- Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
| | - David Sancho
- Immunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
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