IL-10-Dependent Down-Regulation of CXCR3 on Th1 Cells Abolishes Experimental Colitis in Mice

Inflammatory bowel disease (IBD) is characterized by chronic, uncontrolled CD4⁺ T-cell-driven inflammation in the intestinal mucosa. Although the etiology of IBD is poorly understood, it is widely accepted that loss of tolerance to the enteric flora is involved in the development of the disease. Therefore, re-establishing tolerance or gut homeostasis is one of the key features in the development of new therapeutic strategies. Targeting antigen to DEC-205 on dendritic cells (DCs) has been shown to induce tolerance under steady-state conditions. However, whether this approach abrogates inflammatory responses mediated by differentiated Th1 cells is currently unknown. Here we demonstrate that antigen-targeting to DEC-205 protects mice against severe intestinal inflammation by down-regulation  of the chemokine receptor CXCR3 on antigen-specific Th1 cells resulting in abrogated migration of these cells into the gut. Strikingly, this process depends on DC-derived IL-10, since neutralization of IL-10 abolishes protection against inflammation. Moreover, we show that in the inflamed gut mucosa of IBD patients the frequency of CD4⁺CXCR3⁺ T cells is highly elevated compared to non-inflamed tissue. Interference with this pathway may therefore be a promising approach for the treatment of IBD. In summary, we propose a hitherto undescribed mechanism of how antigen-targeting to DEC-205, and more importantly how IL-10 mediates anti-inflammatory properties towards Th1 cells, thereby providing new therapeutic options.