CD69 enhances immunosuppressive function of regulatory T-cells and attenuates colitis by prompting IL-10 production.

Foxp3 regulatory T cells (Tregs) can inhibit immune responses and maintain immune tolerance by secreting immunosuppressive TGF-β1 and IL-10. However, the efficiency of Tregs become the major obstacle to their use for immunotherapy. In this study, we investigated the relevance of the C-type lectin receptor CD69 to the suppressive function. Compared to CD4Foxp3CD69 Tregs (CD69 Tregs), CD4Foxp3CD69 Tregs (CD69 Tregs) displayed stronger ability to maintain immune tolerance. CD69 Tregs expressed higher levels of suppression-associated markers such as CTLA-4, ICOS, CD38 and GITR, and secreted higher levels of IL-10 but not TGF-β1. CD69 Tregs from Il10 rather than Il10 mice significantly inhibit the proliferation of CD4 T cells. CD69 over-expression stimulated higher levels of IL-10 and c-Maf expression, which was compromised by silencing of STAT3 or STAT5. In addition, the direct interaction of STAT3 with the c-Maf promoter was detected in cells with CD69 over-expression. Moreover, adoptive transfer of CD69 Tregs but not CD69Tregs or CD69 Tregs deficient in IL-10 dramatically prevented the development of inflammatory bowel disease (IBD) in mice. Taken together, CD69 is important to the suppressive function of Tregs by promoting IL-10 production. CD69 Tregs have the potential to develop new therapeutic approach for autoimmune diseases like IBD.