Using HLA-DR15-α3 135-145 tetramers, we found that α3 135-145-specific CD4 + T cells in peripheral blood of HLA-DR15 + Goodpasture’s patients are ~100-fold more frequent than in healthy HLA-DR15 + donors. 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 Tregs that leads to protection or causation of autoimmunity. HLA-DR15 + and HLA-DR1 + healthy human donors displayed altered α3 135-145-specific TCR usage, HLA-DR15-α3 135-145 tetramer + Foxp3 − Tconv and HLA-DR1-α3 135-145 tetramer + Foxp3 +CD25 hiCD127 lo Treg dominant phenotypes, and patients with Goodpasture’s disease display a clonally expanded α3 135-145-specific CD4 + T cell repertoire. HLA-DR1-induced Tregs confer resistance to disease in HLA-DR15/DR1 transgenic mice. 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 (Tregs) expressing tolerogenic cytokines. HLA-DR15-α3 135-145 tetramer + T cells in HLA-DR15 transgenic mice exhibit a conventional T cell phenotype (Tconv) that secretes pro-inflammatory cytokines.
HLA-DR15 and HLA-DR1 exhibited distinct peptide repertoires and binding preferences and presented the α3 135-145 epitope in different binding registers. We show that autoreactive α3 135-145-specific T cells expand in patients with Goodpasture’s disease and, in α3 135-145-immunized HLA-DR15 transgenic mice, α3 135-145-specific T cells infiltrate the kidney and mice develop Goodpasture’s disease. While HLA-DR15 confers a markedly increased disease risk, the protective HLA-DR1 allele is dominantly protective in trans with HLA-DR15 2.
Here we investigated the molecular mechanism of Goodpasture’s 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) 1– 4. However, the mechanisms underpinning such HLA-mediated effects on self-tolerance remain unclear.
Susceptibility and protection against human autoimmune diseases, including type I diabetes, multiple sclerosis and Goodpasture’s disease, is associated with particular Human Leukocyte Antigen (HLA) alleles.
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