Dominant HLA-mediated protection from the risk of autoimmune renal disease is conferred by antigen-specific regulatory T cells.

Abstract

Aim: To use Goodpasture's disease (GPD), a classical form of HLA-linked autoimmunity, to define the mechanism of HLA-mediated risk, and dominant protection from risk of disease. Background(s): The mechanisms underpinning HLA-mediated susceptibility to, and protection from autoimmune diseases are unknown. GPD is HLAlinked and characterized by an immunodominant CD4+ self-epitope derived from the alpha3 chain of Type IV collagen (alpha3135-145). Method(s): HLA-DR transgenic mice, cells from HLA-typed healthy humans and from patients with GPD were used, with HLA-DR-alpha3135-145 tetramers, Xray crystallography, and in vivo/in vitro models of autoimmunity. Result(s): Autoreactive alpha3135-145-specific T cells clonally expanded in GPD patients. In alpha3135-145-immunized HLA-DR15 transgenic mice with GPD, alpha3135-145-specific T cells infiltrated the kidney. Structurally, HLA-DR15 and HLA-DR1 presented alpha3135-145 in different binding registers, resulting in differential T cell receptor (TCR) usage. HLA-DR15-alpha3135-145 tetramer+ CD4+ T cells in disease susceptible HLA-DR15 transgenic mice exhibited a conventional phenotype (Tconv), secreting pro-inflammatory cytokines. In contrast, HLA-DR1-alpha3135-145 tetramer+ cells in disease resistant HLA-DR1 and HLADR15/ DR1 transgenic mice were largely CD4+Foxp3+ regulatory T cells (Tregs) expressing tolerogenic cytokines. In HLA-DR15/DR1 transgenic mice, HLA-DR1-alpha3135-145 specific Tregs conferred protection to alpha3135-145-specific autoimmunity and protected from GPD (alpha3135-145-immunized, Treg intact vs Treg depleted: segmental necrosis 0+/-0 vs 50+/-13% P<0.01, serum urea 9+/-1 vs 31+/-10 P<0.001). HLA-DR15+ and HLA-DR1+ healthy human donors displayed altered alpha3135-145-specific TCRs, with HLA-DR15-alpha3135-145 tetramer+ Foxp3- Tconv and HLA-DR1-alpha3135-145 tetramer+ Foxp3+CD25hiCD127lo Treg dominant phenotypes (alpha3135-145 tetramer+ Treg:Tconv ratios: DR15 0.04+/-0.00, DR1 9.61+/-1.79, P<0.001). Conclusion(s): These studies define, for the first time in an autoimmune disease, a mechanism for the dominantly protective effect of HLA, where HLA polymorphisms determine the abundance of self-epitope specific Tregs, leading to protection or causation of autoimmunity.