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 CD4⁺Foxp3⁺CD69⁻ Tregs (CD69⁻ Tregs), CD4⁺Foxp3⁺CD69⁺ 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 CD69⁻Tregs 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.