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 alpha 3 chain of type IV collagen (alpha 3(135-145))(1-4). 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 alpha 3(135-145)-specific T cells expand in patients with Goodpasture disease and, in alpha 3(135-145)-immunized HLA-DR15 transgenic mice, alpha 3(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 alpha 3(135-145) epitope in different binding registers. HLA-DR15-alpha 3(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-alpha 3(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 alpha 3(135-145)-specific T-cell antigen receptor usage, HLA-DR15-alpha 3(135-145) tetramer(+) Foxp3-T-conv and HLA-DR1-alpha 3(135-145) tetramer(+) Foxp3(+) CD25(hi)CD127(lo) T-reg dominant phenotypes. Moreover, patients with Goodpasture disease display a clonally expanded alpha 3(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.