2. Academic Validation
  3. Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells

Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells

  • Nature. 2017 May 11;545(7653):243-247. doi: 10.1038/nature22329.
Joshua D Ooi 1,  Jan Petersen 2 3,  Yu H Tan 2,  Megan Huynh 1,  Zoe J Willett 1,  Sri H Ramarathinam 2,  Peter J Eggenhuizen 1,  Khai L Loh 2,  Katherine A Watson 4,  Poh Y Gan 1,  Maliha A Alikhan 1,  Nadine L Dudek 2,  Andreas Handel 5,  Billy G Hudson 6,  Lars Fugger 7,  David A Power 8 9,  Stephen G Holt 9 10,  P Toby Coates 11,  Jon W Gregersen 12,  Anthony W Purcell 2,  Stephen R Holdsworth 1 13,  Nicole L La Gruta 2 4,  Hugh H Reid 2 3,  Jamie Rossjohn 2 3 14,  A Richard Kitching 1 13 15 16
Affiliations

Affiliations

  • 1 Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria 3168, Australia.
  • 2 Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
  • 3 Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia.
  • 4 Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria 3010, Australia.
  • 5 Department of Epidemiology and Biostatistics, College of Public Health, University of Georgia, Athens, Georgia 30602, USA.
  • 6 Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
  • 7 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.
  • 8 Department of Nephrology, Austin Health, Heidelberg, Victoria 3084, Australia.
  • 9 Department of Medicine, University of Melbourne, Melbourne, Victoria 3010, Australia.
  • 10 Department of Nephrology, The Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
  • 11 Central Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, Adelaide, South Australia 5000, Australia.
  • 12 Department of Medicine, Viborg Regional Hospital, Viborg 8800, Denmark.
  • 13 Department of Nephrology, Monash Health, Clayton, Victoria 3168, Australia.
  • 14 Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
  • 15 NHMRC Centre for Personalised Immunology, Monash University, Clayton, Victoria 3168, Australia.
  • 16 Department of Pediatric Nephrology, Monash Health, Victoria 3168, Australia.
PMID: 28467828 DOI: 10.1038/nature22329
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.

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