Reference
Reference TypeLiterature
TitleDominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells.
AuthorsJoshua D Ooi; Jan Petersen; Yu H Tan; Megan Huynh; Zoe J Willett; Sri H Ramarathinam; Peter J Eggenhuizen; Khai L Loh; Katherine A Watson; Poh Y Gan; Maliha A Alikhan; Nadine L Dudek; Andreas Handel; Billy G Hudson; Lars Fugger; David A Power; Stephen G Holt; P Toby Coates; Jon W Gregersen; Anthony W Purcell; Stephen R Holdsworth; Nicole L La Gruta; Hugh H Reid; Jamie Rossjohn; A Richard Kitching
AffiliationsCentre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, 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; 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 3084, Australia; Department of Medicine, Univers...
JournalNature
Year2017
AbstractSusceptibility 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<sup>+</sup> T-cell self-epitope derived from the 3 chain of type IV collagen (3<sub>135-145</sub>). 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 3<sub>135-145</sub>-specific T cells expand in patients with Goodpasture disease and, in 3<sub>135-145</sub>-immunized HLA-DR15 transgenic mice, 3<sub>135-145</sub>-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 3<sub>135-145</sub> epitope in different binding registers. HLA-DR15-3<sub>135-145</sub> tetramer<sup>+</sup> T cells in HLA-DR15 transgenic mice exhibit a conventional T-cell phenotype (T<sub>conv</sub>) that secretes pro-inflammatory cytokines. In contrast, HLA-DR1-3<sub>135-145</sub> tetramer<sup>+</sup> T cells in HLA-DR1 and HLA-DR15/DR1 transgenic mice are predominantly CD4<sup>+</sup>Foxp3<sup>+</sup> regulatory T cells (T<sub>reg</sub> cells) expressing tolerogenic cytokines. HLA-DR1-induced T<sub>reg</sub> cells confer resistance to disease in HLA-DR15/DR1 transgenic mice. HLA-DR15<sup>+</sup> and HLA-DR1<sup>+</sup> healthy human donors display altered 3<sub>135-145</sub>-specific T-cell antigen receptor usage, HLA-DR15-3<sub>135-145</sub> tetramer<sup>+</sup> Foxp3<sup>-</sup> T<sub>conv</sub> and HLA-DR1-3<sub>135-145</sub> tetramer<sup>+</sup> Foxp3<sup>+</sup>CD25<sup>hi</sup>CD127<sup>lo</sup> T<sub>reg</sub> dominant phenotypes. Moreover, patients with Goodpasture disease display a clonally expanded 3<sub>135-145</sub>-specific CD4<sup>+</sup> 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<sub>reg</sub> cells that leads to protection or causation of autoimmunity.
Curation Last Updated2025-02-10 19:45:53
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