| First Author | Ooi JD | Year | 2017 |
| Journal | Nature | Volume | 545 |
| Issue | 7653 | Pages | 243-247 |
| PubMed ID | 28467828 | Mgi Jnum | J:252521 |
| Mgi Id | MGI:6093496 | Doi | 10.1038/nature22329 |
| Citation | Ooi JD, et al. (2017) Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells. Nature 545(7653):243-247 |
| abstractText | 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 alpha3 chain of type IV collagen (alpha3135-145). 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 alpha3135-145-specific T cells expand in patients with Goodpasture disease and, in alpha3135-145-immunized HLA-DR15 transgenic mice, alpha3135-145-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 alpha3135-145 epitope in different binding registers. HLA-DR15-alpha3135-145 tetramer(+) T cells in HLA-DR15 transgenic mice exhibit a conventional T-cell phenotype (Tconv) that secretes pro-inflammatory cytokines. In contrast, HLA-DR1-alpha3135-145 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 alpha3135-145-specific T-cell antigen receptor usage, HLA-DR15-alpha3135-145 tetramer(+) Foxp3(-) Tconv and HLA-DR1-alpha3135-145 tetramer(+) Foxp3(+)CD25(hi)CD127(lo) Treg dominant phenotypes. Moreover, patients with Goodpasture disease display a clonally expanded alpha3135-145-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. |
