Pathogenic role for γδ T cells in autoimmune anti-myeloperoxidase glomerulonephritis

Myeloperoxidase (MPO) anti-neutrophil cytoplasmic Ab (ANCA)-associated vasculitis results from autoimmunity to MPO. IL-17A plays a critical role in generating this form of autoimmune injury but its cell of origin is uncertain. We addressed the hypothesis that IL-17A-producing gd T cells are a nonredundant requisite in the development of MPO autoimmunity and glomerulonephritis (GN).We studied MPO-ANCA GN in wild type, ab, or gd T cell-deficient (C57BL/6, bTCR2/2, and dTCR2/2 respectively) mice. Both T cell populations played important roles in the generation of autoimmunity to MPO and GN. Humoral autoimmunity was dependent on intact ab T cells but was unaffected by gd T cell deletion. Following MPO immunization, activated gd T cells migrate to draining lymph nodes. Studies in dTCR2/2 and transfer of gd T cells to dTCR2/2 mice show that gd T cells facilitate the generation of anti-MPO autoimmunity and GN. dTCR2/2 mice that received IL-17A2/2 gd T cells demonstrate that the development of anti-MPO autoimmunity and GN are dependent on gd T cell IL-17A production. Finally, transfer of anti-MPO CD4⁺ T cell clones to naive dTCR2/2 and wild type mice with planted glomerular MPO shows that gd T cells are also necessary for recruitment of anti-MPO ab CD4⁺ effector T cells. This study demonstrates that IL-17A produced by gd T cells plays a critical role in the pathogenesis of MPO-ANCA GN by promoting the development of MPO-specific ab T cells.