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

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.