PMID- 28467828 OWN - NLM STAT- MEDLINE DCOM- 20170908 LR - 20181113 IS - 1476-4687 (Electronic) IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 545 IP - 7653 DP - 2017 May 11 TI - Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells. PG - 243-247 LID - 10.1038/nature22329 [doi] AB - Susceptibility and protection against human autoimmune diseases, including type I diabetes, multiple sclerosis, and Goodpasture disease, is associated with particular human leukocyte antigen (HLA) alleles. However, the mechanisms underpinning such HLA-mediated effects on self-tolerance remain unclear. Here we investigate the molecular mechanism of Goodpasture disease, an HLA-linked autoimmune renal disorder characterized by an immunodominant CD4(+) T-cell self-epitope derived from the alpha3 chain of type IV collagen (alpha3(135-145)). While HLA-DR15 confers a markedly increased disease risk, the protective HLA-DR1 allele is dominantly protective in trans with HLA-DR15 (ref. 2). We show that autoreactive alpha3(135-145)-specific T cells expand in patients with Goodpasture disease and, in alpha3(135-145)-immunized HLA-DR15 transgenic mice, alpha3(135-145)-specific T cells infiltrate the kidney and mice develop Goodpasture disease. HLA-DR15 and HLA-DR1 exhibit distinct peptide repertoires and binding preferences and present the alpha3(135-145) epitope in different binding registers. HLA-DR15-alpha3(135-145) tetramer(+) T cells in HLA-DR15 transgenic mice exhibit a conventional T-cell phenotype (T(conv)) that secretes pro-inflammatory cytokines. In contrast, HLA-DR1-alpha3(135-145) tetramer(+) T cells in HLA-DR1 and HLA-DR15/DR1 transgenic mice are predominantly CD4(+)Foxp3(+) regulatory T cells (T(reg) cells) expressing tolerogenic cytokines. HLA-DR1-induced T(reg) cells confer resistance to disease in HLA-DR15/DR1 transgenic mice. HLA-DR15(+) and HLA-DR1(+) healthy human donors display altered alpha3(135-145)-specific T-cell antigen receptor usage, HLA-DR15-alpha3(135-145) tetramer(+) Foxp3(-) T(conv) and HLA-DR1-alpha3(135-145) tetramer(+) Foxp3(+)CD25(hi)CD127(lo) T(reg) dominant phenotypes. Moreover, patients with Goodpasture disease display a clonally expanded alpha3(135-145)-specific CD4(+) T-cell repertoire. Accordingly, we provide a mechanistic basis for the dominantly protective effect of HLA in autoimmune disease, whereby HLA polymorphism shapes the relative abundance of self-epitope specific T(reg) cells that leads to protection or causation of autoimmunity. FAU - Ooi, Joshua D AU - Ooi JD AD - Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria 3168, Australia. FAU - Petersen, Jan AU - Petersen J AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. AD - Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia. FAU - Tan, Yu H AU - Tan YH AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. FAU - Huynh, Megan AU - Huynh M AD - Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria 3168, Australia. FAU - Willett, Zoe J AU - Willett ZJ AD - Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria 3168, Australia. FAU - Ramarathinam, Sri H AU - Ramarathinam SH AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. FAU - Eggenhuizen, Peter J AU - Eggenhuizen PJ AD - Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria 3168, Australia. FAU - Loh, Khai L AU - Loh KL AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. FAU - Watson, Katherine A AU - Watson KA AD - Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria 3010, Australia. FAU - Gan, Poh Y AU - Gan PY AD - Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria 3168, Australia. FAU - Alikhan, Maliha A AU - Alikhan MA AD - Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria 3168, Australia. FAU - Dudek, Nadine L AU - Dudek NL AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. FAU - Handel, Andreas AU - Handel A AD - Department of Epidemiology and Biostatistics, College of Public Health, University of Georgia, Athens, Georgia 30602, USA. FAU - Hudson, Billy G AU - Hudson BG AD - Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA. FAU - Fugger, Lars AU - Fugger L AD - Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, and MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK. FAU - Power, David A AU - Power DA AD - Department of Nephrology, Austin Health, Heidelberg, Victoria 3084, Australia. AD - Department of Medicine, University of Melbourne, Melbourne, Victoria 3010, Australia. FAU - Holt, Stephen G AU - Holt SG AD - Department of Medicine, University of Melbourne, Melbourne, Victoria 3010, Australia. AD - Department of Nephrology, The Royal Melbourne Hospital, Parkville, Victoria 3050, Australia. FAU - Coates, P Toby AU - Coates PT AD - Central Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, Adelaide, South Australia 5000, Australia. FAU - Gregersen, Jon W AU - Gregersen JW AD - Department of Medicine, Viborg Regional Hospital, Viborg 8800, Denmark. FAU - Purcell, Anthony W AU - Purcell AW AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. FAU - Holdsworth, Stephen R AU - Holdsworth SR AD - Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria 3168, Australia. AD - Department of Nephrology, Monash Health, Clayton, Victoria 3168, Australia. FAU - La Gruta, Nicole L AU - La Gruta NL AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. AD - Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria 3010, Australia. FAU - Reid, Hugh H AU - Reid HH AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. AD - Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia. FAU - Rossjohn, Jamie AU - Rossjohn J AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia. AD - Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia. AD - Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK. FAU - Kitching, A Richard AU - Kitching AR AD - Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria 3168, Australia. AD - Department of Nephrology, Monash Health, Clayton, Victoria 3168, Australia. AD - NHMRC Centre for Personalised Immunology, Monash University, Clayton, Victoria 3168, Australia. AD - Department of Pediatric Nephrology, Monash Health, Victoria 3168, Australia. LA - eng GR - R01 DK018381/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170503 PL - England TA - Nature JT - Nature JID - 0410462 RN - 0 (Collagen Type IV) RN - 0 (Cytokines) RN - 0 (Forkhead Transcription Factors) RN - 0 (Foxp3 protein, mouse) RN - 0 (HLA-DR Serological Subtypes) RN - 0 (HLA-DR1 Antigen) RN - 0 (HLA-DR15 antigen) RN - 0 (Immunodominant Epitopes) SB - IM CIN - Nat Rev Nephrol. 2017 Jul;13(7):381. PMID: 28502986 CIN - Nat Rev Rheumatol. 2017 Jul;13(7):387. PMID: 28515462 MH - Animals MH - Anti-Glomerular Basement Membrane Disease/*immunology/pathology MH - Autoimmunity/*immunology MH - Base Sequence MH - CD4-Positive T-Lymphocytes/immunology MH - Collagen Type IV/chemistry/immunology MH - Cytokines/immunology MH - Female MH - Forkhead Transcription Factors/metabolism MH - HLA-DR Serological Subtypes/immunology MH - HLA-DR1 Antigen/immunology MH - Humans MH - Immunodominant Epitopes MH - Male MH - Mice MH - Mice, Transgenic MH - Models, Molecular MH - T-Lymphocytes, Regulatory/*immunology PMC - PMC5903850 MID - NIHMS955657 COIS- The authors declare no competing interests. EDAT- 2017/05/04 06:00 MHDA- 2017/09/09 06:00 PMCR- 2018/05/11 CRDT- 2017/05/04 06:00 PHST- 2016/09/19 00:00 [received] PHST- 2017/03/31 00:00 [accepted] PHST- 2017/05/04 06:00 [pubmed] PHST- 2017/09/09 06:00 [medline] PHST- 2017/05/04 06:00 [entrez] PHST- 2018/05/11 00:00 [pmc-release] AID - nature22329 [pii] AID - 10.1038/nature22329 [doi] PST - ppublish SO - Nature. 2017 May 11;545(7653):243-247. doi: 10.1038/nature22329. Epub 2017 May 3.