CXCR3 mediates renal Th1 and Th17 immune response in murine lupus nephritis.

Infiltration of T cells into the kidney is a typical feature of human and experimental lupus nephritis that contributes to renal tissue injury. The chemokine receptor CXCR3 is highly expressed on Th1 cells and is supposed to be crucial for their trafficking into inflamed tissues. In this study, we explored the functional role of CXCR3 using the MRL/MpJ-Fas(lpr) (MRL/lpr) mouse model of systemic lupus erythematosus that closely resembles the human disease. CXCR3(-/-) mice were generated and backcrossed into the MRL/lpr background. Analysis of 20-wk-old CXCR3(-/-) MRL/lpr mice showed amelioration of nephritis with reduced glomerular tissue damage and decreased albuminuria and T cell recruitment. Most importantly, not only the numbers of renal IFN-gamma-producing Th1 cells, but also of IL-17-producing Th17 cells were significantly reduced. Unlike in inflamed kidneys, there was no reduction in the numbers of IFN-gamma- or IL-17-producing T cells in spleens, lymph nodes, or the small intestine of MRL/lpr CXCR3(-/-) mice. This observation suggests impaired trafficking of effector T cells to injured target organs, rather than the inability of CXCR3(-/-) mice to mount efficient Th1 and Th17 immune responses. These findings show a crucial role for CXCR3 in the development of experimental lupus nephritis by directing pathogenic effector T cells into the kidney. For the first time, we demonstrate a beneficial effect of CXCR3 deficiency through attenuation of both the Th1 and the newly defined Th17 immune response. Our data therefore identify the chemokine receptor CXCR3 as a promising therapeutic target in lupus nephritis.