Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells PMID: 28467828

ADC Targets in Oncology

2026-04-10

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

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.

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 (α3_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 α3_135-145-specific T cells expand in patients with Goodpasture disease and, in α3_135-145-immunized HLA-DR15 transgenic mice, α3_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 α3_135-145 epitope in different binding registers. HLA-DR15-α3_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-α3_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 α3_135-145-specific T-cell antigen receptor usage, HLA-DR15-α3_135-145 tetramer⁺ Foxp3^- T_conv and HLA-DR1-α3_135-145 tetramer⁺ Foxp3⁺CD25^hiCD127^lo T_reg dominant phenotypes. Moreover, patients with Goodpasture disease display a clonally expanded α3_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.