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-g, 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 byMPO-specific CD4⁺ cells in Rag1^-/- mice. Transfer ofMPO_431-439-specificCD8+ cellswithout CD4⁺ cellsmediated glomerular injury whenMPOwas planted in glomeruli. These results show a pathogenic role forMPO- 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.