IL-1β/p38 signaling controls IL-17 production by T regulatory cells (139.3)

Abstract

Abstract T regulatory (Treg) cells expressing Foxp3 represent a distinct lineage of T lymphocytes committed to suppressive functions. Recent studies have shown that Treg cells can become IL-17 producers in the context of inflammatory cytokine milieu similarly to conventional CD4+ T cells (Tconv). In the present study, we studied the differentiation of IL-17 producing cells in the absence of exogenous cytokines and insults. We showed that under neutral culture conditions, simultaneous activation of naïve Tconv cells and Treg cells in the presence of antigen presenting cells (APC) promoted conversion of Treg but not Tconv into IL-17 producing cells. Using both an in vitro culture system and an in vivo model, we determined that endogenous IL-1β but not IL-6 played an essential role in the conversion process. Mechanistic analysis revealed that IL-1β induced strong activation of p38 MAPK in Treg but not in Tconv cells. Addition of the p38 inhibitor SB203580 in the co-culture abrogated the production of IL-17A by Treg cells, indicating that p38 downstream pathways might be responsible for regulating production of IL-17 by Treg. Our findings indicate that Treg cells are subjected to regulation that is mediated through APC and activated Tconv and reveal a central role of IL-1β and p38 MAPK in this process. These observations provide a new dimension to our understanding of Treg functions and may have important implications in therapeutic strategies using Treg cells.