Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells
Open accessAbstract
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 hi CD127 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.
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- Authors
- Ooi, J. D., Petersen, J., Tan, Y. H., Huynh, M., Willett, Z. J., Ramarathinam, S. H., Eggenhuizen, P. J., Loh, K. L., Watson, K. A., Gan, P. Y., Alikhan, M. A., Dudek, N. L., Handel, A., Hudson, B. G., Fugger, L., Power, D. A., Holt, S. G., Coates, P. T., Gregersen, J. W., Purcell, A. W., Holdsworth, S. R., La Gruta, N. L., Reid, H. H., Rossjohn, J., & Kitching, A. R.
- Affiliations
- Monash Medical Centre (AU)
- Monash University (AU)
- The University of Melbourne (AU)
- University of Georgia (US)
- Vanderbilt University Medical Center (US)
- John Radcliffe Hospital (GB)
- The Royal Melbourne Hospital (AU)
- Royal Adelaide Hospital (AU)
- Regionshospitalet Viborg (DK)
- Corresponding author
- Reid, Hugh H.
- Rossjohn, Jamie
- Kitching, A. Richard
- ORCID
- Ooi, Joshua D.
- Petersen, Jan
- Huynh, Megan
- Ramarathinam, Sri H.
- Eggenhuizen, Peter J.
- Loh, Khai L.
- Watson, Katherine A.
- Gan, Poh Y.
- Alikhan, Maliha A.
- Handel, Andreas
- Hudson, Billy G.
- Fugger, Lars
- Power, David A.
- Holt, Stephen G.
- Coates, P. Toby
- Gregersen, Jon W.
- Purcell, Anthony W.
- Reid, Hugh H.
- Rossjohn, Jamie
- Kitching, A. Richard
- Venue
- Nature
- Published
- 2017-05
- Volume
- 545
- Issue
- 7653
- Pages
- 243-247
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5903850
- OpenAlex
- W2611932423
- Cited by
- 218
- References
- 38
- Citations by year
- 2026: 16 · 2025: 12 · 2024: 23 · 2023: 17 · 2022: 23 · 2021: 22 · 2020: 32 · 2019: 31 · 2018: 32 · 2017: 9
- FWCI
- 12.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK018381)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Keywords
- HLA-DR1, HLA-DR15, regulatory T cells, antigen-specific regulatory T cells, autoreactive T cells, self-tolerance, MHC class II
- MeSH terms
- Animals, Base Sequence, Female, Humans, Male, Mice, Transgenic, Models, Molecular, CD4-Positive T-Lymphocytes, Autoimmunity, HLA-DR1 Antigen, Immunodominant Epitopes, Cytokines, Anti-Glomerular Basement Membrane Disease, Collagen Type IV, T-Lymphocytes, Regulatory, Mice, Forkhead Transcription Factors, HLA-DR Serological Subtypes
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