Distinct inflammatory signals have physiologically divergent effects on epigenetic regulation of Foxp3 expression and Treg function.

Foxp3 expression in regulatory T cells (Treg) is required for development and suppressive function. How different inflammatory signals affect Foxp3 chromatin structure, expression, and Tregs plasticity are not completely known. In the present study, the Toll-like receptor 2 (TLR2) ligand peptidoglycan inhibited Foxp3 expression in both natural Treg (nTreg) and TGFβ-driven adaptive Treg (aTreg). Inhibition was independent of paracrine Th1, Th2 and Th17 cytokines. PGN-induced T cell intrinsic TLR2-Myd88 dependent IFR1 expression, and induced IRF1 bound to IRF1 response elements (IRF-E) in the Foxp3 promoter and intronic enhancers, and negatively regulated Foxp3 expression. Inflammatory IL-6 and TLR2 signals induced divergent chromatin changes at the Foxp3 locus and regulated Treg suppressor function, and in an islet transplant model resulted in differences in their ability to prolong graft survival. These findings are important for understanding how different inflammatory signals can affect the transplantation tolerance and immunity.