CD8+ T Cells Effect Glomerular Injury in Experimental Anti-Myeloperoxidase GN

Abstract

Observations in patients with ANCA-associated vasculitis suggest that CD8⁺ T cells participate in disease, but there is no experimental functional evidence of pathologic involvement for these cells. Myeloperoxidase (MPO) is a well defined autoantigen in ANCA-associated vasculitis. Studies in experimental models of anti-MPO GN suggest that, after ANCA-induced neutrophil localization, deposited MPO within glomeruli is recognized by autoreactive T cells that contribute to injury. We tested the hypothesis that CD8⁺ T cells mediate disease in experimental ANCA-associated vasculitis. CD8⁺ T cell depletion in the effector phase of disease attenuated injury in murine anti-MPO GN. This protection associated with decreased levels of intrarenal IFN-γ, TNF, and inflammatory chemokines and fewer glomerular macrophages. Moreover, we identified a pathogenic CD8⁺ T cell MPO epitope (MPO_431-439) and found that cotransfer of MPO_431-439-specific CD8⁺ T cell clones exacerbated disease mediated by MPO-specific CD4⁺ cells in Rag1^-/- mice. Transfer of MPO_431-439-specific CD8⁺ cells without CD4⁺ cells mediated glomerular injury when MPO was planted in glomeruli. These results show a pathogenic role for MPO-specific CD8⁺ T cells, provide evidence that CD8⁺ cells are a therapeutic target in ANCA-associated vasculitis, and suggest that a molecular hotspot within the MPO molecule contains important CD8⁺, CD4⁺, and B cell epitopes.