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

Pathogens

Natarajan Bhaskaran²  Samuel Cohen²  Yifan Zhang²  Aaron Weinberg²  Pushpa Pandiyan¹ 

[1] Department of Biological Sciences, School of Dental Medicine, Casfe Western Reserve University, Cleveland, OH 44106, USA;

关键词: T_reg;    Foxp3;    Th17;    IL-17A;    TLR ligands;    TLR-2;    Candida albicans;    IBD;   

DOI  :  10.3390/pathogens4010090

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.