MHC class I pathway is not required for the development of crescentic glomerulonephritis in mice

Abstract

SUMMARY MHC II and CD4+ T cells are required for anti-glomerular basement membrane (GBM) globulin-initiated crescentic glomerulonephritis (GN) in mice, but the role of MHC I and CD8+ T cells is unclear. The cytolytic function of CD8+ T cells requires recognition of peptide antigens presented on MHC I. CD8+ T cells can also perform helper functions via cytokine production. The contribution of MHC I to crescentic GN was investigated using TAP-1 gene knock out (TAP-1−/−) mice, which have deficient MHC I antigen presentation. Heterozygous TAP-1 mice have normal MHC I expression and developed GN with crescents in 42 ± 4% of glomeruli (normal 0%), proteinuria (9·1 ± 1·6 mg/20 h, normal 1·5 ± 0·3 mg/20 h) and impaired renal function (creatinine clearance 110 ± 8 μl/min, normal 193 ± 10 μl/min) following administration of sheep anti-mouse GBM globulin. TAP-1−/− mice, which have extremely low MHC I expression and reduced CD8+ T cells, developed similar GN with 39 ± 3% crescents, proteinuria (12·7 ± 4·3 mg/20 h) and impaired renal function (creatinine clearance 123 ± 20 μl/min). In vivo antibody-induced CD8 depletion did not attenuate crescent formation or protect renal function in C57Bl/6 mice developing GN, although significant reduction in proteinuria (5·3 ± 1·2 mg/20 h, P = 0·012) and glomerular recruitment of CD4+ T cells and macrophages were observed compared with control treated mice with GN. These data demonstrate that MHC I is not required for development of crescentic GN in mice. The MHC I-independent contribution of CD8+ T cells to proteinuria and inflammatory cell recruitment suggests that they may serve a ‘helper’ rather than cytolytic role in this disease.