Elucidating the Role of CD27 in Treg Function during Th17 Responses

Abstract

Abstract Tregs and Th17 cells have a very close and complex relationship. Tregs and Th17 cells share a dependence on TGFb for their differentiation and it has recently been shown that Tregs require the Th17-driving transcription factor STAT3 to regulate Th17 responses. Despite sharing a dependence on STAT3, Tregs within healthy tissue tend to produce very low amounts of IL-17. In contrast, in multiple Th17-driven diseases (including Multiple Sclerosis, Psoriasis and Crohn’s) Tregs within the diseased tissue produce increased levels of the IL-17. The costimulatory receptor CD27 and its ligand, CD70, have been shown to play a role in suppressing Th17 responses through the epigenetic suppression of IL-17 and CCR6. We have found that CD27 is highly expressed on Tregs in both human and murine skin, but whether CD27 plays a role in promoting Treg function (and suppressing acquisition of Th17-like traits) remains unknown. Utilizing CD27-deficient mice (CD27KO), we found that Tregs in the skin of CD27KO mice in the steady state produced more IL-17 compared to their wild-type (WT) counterparts. To test the role of CD27 specifically on Tregs during Th17-driven inflammation in vivo, we have developed an adoptive transfer model of cutaneous candida albicans infection where Tregs play an essential role in the development of productive Th17 responses. Using this model, we found that CD27 suppressed Treg expression of IL-17 and CCR6 in a cell-intrinsic manner. We also found that IL-6 could induce the production of IL-17 from Tregs in vitro which was suppressed when co-cultured with CD70 expressing BMDCs. Our studies suggest that the CD27-CD70 pathway promotes Treg function by limiting production of Th17 effector molecules.