Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/18979
Title: Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells.
Authors: Ooi, Joshua D;Petersen, Jan;Tan, Yu H;Huynh, Megan;Willett, Zoe J;Ramarathinam, Sri H;Eggenhuizen, Peter J;Loh, Khai L;Watson, Katherine A;Gan, Poh Y;Alikhan, Maliha A;Dudek, Nadine L;Handel, Andreas;Hudson, Billy G;Fugger, Lars;Power, David Anthony;Holt, Stephen G;Coates, P Toby;Gregersen, Jon W;Purcell, Anthony W;Holdsworth, Stephen R;La Gruta, Nicole L;Reid, Hugh H;Rossjohn, Jamie;Kitching, A Richard
Affiliation: Department of Pediatric Nephrology, Monash Health, Victoria 3168, Australia
Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
NHMRC Centre for Personalised Immunology, Monash University, Clayton, Victoria 3168, Australia
Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia
Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria 3010, Australia
Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria 3168, Australia
Department of Epidemiology and Biostatistics, College of Public Health, University of Georgia, Athens, Georgia 30602, USA
Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
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
Department of Nephrology, Austin Health, Heidelberg, Victoria, Australia
Department of Medicine, University of Melbourne, Melbourne, Victoria 3010, Australia
Department of Nephrology, The Royal Melbourne Hospital, Parkville, Victoria 3050, Australia
Central Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, Adelaide, South Australia 5000, Australia
Department of Medicine, Viborg Regional Hospital, Viborg 8800, Denmark
Department of Nephrology, Monash Health, Clayton, Victoria 3168, Australia
Issue Date: 11-May-2017
EDate: 2017-05-03
Citation: Nature 2017; 545(7653): 243-247
Abstract: 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 α3 chain of type IV collagen (α3135-145). 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 α3135-145-specific T cells expand in patients with Goodpasture disease and, in α3135-145-immunized HLA-DR15 transgenic mice, α3135-145-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 α3135-145 epitope in different binding registers. HLA-DR15-α3135-145 tetramer+ T cells in HLA-DR15 transgenic mice exhibit a conventional T-cell phenotype (Tconv) that secretes pro-inflammatory cytokines. In contrast, HLA-DR1-α3135-145 tetramer+ T cells in HLA-DR1 and HLA-DR15/DR1 transgenic mice are predominantly CD4+Foxp3+ regulatory T cells (Treg cells) expressing tolerogenic cytokines. HLA-DR1-induced Treg cells confer resistance to disease in HLA-DR15/DR1 transgenic mice. HLA-DR15+ and HLA-DR1+ healthy human donors display altered α3135-145-specific T-cell antigen receptor usage, HLA-DR15-α3135-145 tetramer+ Foxp3- Tconv and HLA-DR1-α3135-145 tetramer+ Foxp3+CD25hiCD127lo Treg dominant phenotypes. Moreover, patients with Goodpasture disease display a clonally expanded α3135-145-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 Treg cells that leads to protection or causation of autoimmunity.
URI: http://ahro.austin.org.au/austinjspui/handle/1/18979
DOI: 10.1038/nature22329
PubMed URL: 28467828
Type: Journal Article
Research Support, Non-U.S. Gov't
Appears in Collections:Journal articles

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