HLA class II histocompatibility antigen, DR alpha chain
positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation
Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells.
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<sup>+</sup> T-cell self-epitope derived from the α3 chain of type IV collagen (α3<sub>135-145</sub>). 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<sub>135-145</sub>-specific T cells expand in patients with Goodpasture disease and, in α3<sub>135-145</sub>-immunized HLA-DR15 transgenic mice, α3<sub>135-145</sub>-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<sub>135-145</sub> epitope in different binding registers. HLA-DR15-α3<sub>135-145</sub> tetramer<sup>+</sup> T cells in HLA-DR15 transgenic mice exhibit a conventional T-cell phenotype (T<sub>conv</sub>) that secretes pro-inflammatory cytokines. In contrast, HLA-DR1-α3<sub>135-145</sub> tetramer<sup>+</sup> T cells in HLA-DR1 and HLA-DR15/DR1 transgenic mice are predominantly CD4<sup>+</sup>Foxp3<sup>+</sup> regulatory T cells (T<sub>reg</sub> cells) expressing tolerogenic cytokines. HLA-DR1-induced T<sub>reg</sub> cells confer resistance to disease in HLA-DR15/DR1 transgenic mice. HLA-DR15<sup>+</sup> and HLA-DR1<sup>+</sup> healthy human donors display altered α3<sub>135-145</sub>-specific T-cell antigen receptor usage, HLA-DR15-α3<sub>135-145</sub> tetramer<sup>+</sup> Foxp3<sup>-</sup> T<sub>conv</sub> and HLA-DR1-α3<sub>135-145</sub> tetramer<sup>+</sup> Foxp3<sup>+</sup>CD25<sup>hi</sup>CD127<sup>lo</sup> T<sub>reg</sub> dominant phenotypes. Moreover, patients with Goodpasture disease display a clonally expanded α3<sub>135-145</sub>-specific CD4<sup>+</sup> 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<sub>reg</sub> cells that leads to protection or causation of autoimmunity.