Pathogenic Role for γδ T Cells in Autoimmune Anti-Myeloperoxidase Glomerulonephritis

Abstract

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 γδ T cells are a nonredundant requisite in the development of MPO autoimmunity and glomerulonephritis (GN). We studied MPO-ANCA GN in wild type, αβ, or γδ T cell-deficient (C57BL/6, , and respectively) mice. Both T cell populations played important roles in the generation of autoimmunity to MPO and GN. Humoral autoimmunity was dependent on intact αβ T cells but was unaffected by γδ T cell deletion. Following MPO immunization, activated γδ T cells migrate to draining lymph nodes. Studies in and transfer of γδ T cells to mice show that γδ T cells facilitate the generation of anti-MPO autoimmunity and GN. mice that received γδ T cells demonstrate that the development of anti-MPO autoimmunity and GN are dependent on γδ T cell IL-17A production. Finally, transfer of anti-MPO CD4 T cell clones to naive and wild type mice with planted glomerular MPO shows that γδ T cells are also necessary for recruitment of anti-MPO αβ CD4 effector T cells. This study demonstrates that IL-17A produced by γδ T cells plays a critical role in the pathogenesis of MPO-ANCA GN by promoting the development of MPO-specific αβ T cells.

Animal Models of ANCA Associated Vasculitis

“…Unconventional γδ T cells, also a source of IL-17A, play a role in glomerular T cell and neutrophil recruitment. Mice genetically deficient in γδ T cells developed less severe disease compared to wild type mice (91).…”

GILZ Regulates the Expression of Pro-Inflammatory Cytokines and Protects Against End-Organ Damage in a Model of Lupus

“…Glomerular damage was scored in a blinded manner for segmental necrosis (shown as percentage of glomeruli affected) and crescent formation as described (25). IgG and C3 immunofluorescence staining were given an intensity score between 0-3, and an average of 20 glomeruli were scored for each mouse.…”

T-lymphocyte in ANCA-associated vasculitis: what do we know? A pathophysiological and therapeutic approach

“…T-cells carrying γδ-chain TCR are involved in innate host defence and can produce IL-17. The role of these IL-17-producing, γδ-chain TCR-expressing T-cells in AAV has been addressed in murine models [58, 59]. In γ and δ chain knock-out murine models, structural and glomerular injury is attenuated.…”