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-γt 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.