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. ). 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.