Regulation of organ-specific inflammation by CXCR5 during systemic autoimmunity (BA13P.131)

Abstract

Abstract Mice and humans deficient in the Foxp3+ T regulatory cells (Tregs) develop systemic autoimmunity affecting multiple organs and die prematurely. Mice deficient for interleukin (IL)-2 (IL2KO) have reduced Tregs and develop inflammation mainly in liver, colon, pancreas and salivary glands. We found that the CD4+ T-cells in the secondary lymphoid organs IL2KO mice highly express CXCR5, a chemokine receptor and a marker for T-follicular helper (TfH) cells. We hypothesized that CXCR5 expression may regulate inflammation by regulating T-cell recruitment and organ-specific autoantibody production. We found that CXCR5+CD4+ T-cells were highly enriched in these inflamed organs of IL2KO mice. Rendering the IL2KO mice deficient for CXCR5 led to prolonged lifespan compared to CXCR5-sufficient IL2KO mice and protection against inflammation especially in liver and colon and partial protection against inflammation in pancreas and salivary glands. This was accompanied with a reduction of activated B and T cells in the secondary lymphoid organs as well as reduced production of inflammatory cytokines by the T-cells. However, no significant correlation was observed between CXCR5 expression and antibodies to liver and pancreatic auto-antigens. The data suggests that CXCR5 expression regulates organ-specific inflammation during Treg-deficiency -induced systemic autoimmunity, through regulation of T-cell trafficking, with an undetectable contribution to autoantibody production.