TLR-2 Signaling Promotes IL-17A Production in CD4+CD25+Foxp3+ Regulatory Cells during Oropharyngeal Candidiasis

Recent studies show that CD4(+)CD25(+)Foxp3(+) regulatory cells (T-regs) produce effector cytokines under inflammatory conditions. However, the direct role of microbial agents that serve as toll-like receptor (TLR) ligands in the induction of effector cytokines in T-regs is less clear. Here we show that CD4(+)Foxp3(+)T(regs) produce the effector cytokine IL-17A during oropharyngeal candidiasis (OPC) and inflammatory bowel disease in a TLR-2/Myd88 signaling dependent manner. TLR-2 ligands promote proliferation in T-regs in the presence and absence of TCR signals and inflammatory cytokines in vitro. The proliferation is directly dependent on TLR-2 expression in T-regs. Consistent with this, Tlr2(-/-) mice harbor fewer thymically derived T-regs and peripheral T-regs under homeostatic conditions in vivo. However, under Th17 inducing conditions, IL-6 and TLR-2 signaling both in T-regs as well as antigen presenting cells (APC) are critical for maximal ROR-t and IL-17A up-regulation in Foxp3(+) T-regs. The minimal and transient loss of Foxp3 expression and suppressive properties are due to the presence of IL-6 in the milieu, but not the direct effect of TLR-2 signaling in T-regs. Taken together, our data reveal that TLR-2 signaling promotes not only proliferation, but also IL-17A in T-regs, depending on the cytokine milieu. These IL-17A producing T-regs may be relevant in mucosal infections and inflammation.