Cutting Edge: An In Vivo Requirement for STAT3 Signaling in TH17 Development and TH17-Dependent Autoimmunity

Abstract

STAT3 activation has been observed in several autoimmune diseases, suggesting that STAT3-mediated pathways promote pathologic immune responses. We provide in vivo evidence that the fundamental role of STAT3 signaling in autoimmunity relates to its absolute requirement for generating TH17 T cell responses. We show that STAT3 is a master regulator of this pathogenic T cell subtype, acting at multiple levels in vivo, including TH17 T cell differentiation and cytokine production, as well as induction of RORγt and the IL-23R. Neither naturally occurring TH17 cells nor TH17-dependent autoimmunity occurs when STAT3 is ablated in CD4 cells. Furthermore, ablation of STAT3 signaling in CD4 cells results in increased TH1 responses, indicating that STAT3 signaling skews TH responses away from the TH1 pathway and toward the TH17 pathway. Thus, STAT3 is a candidate target for TH17-dependent autoimmune disease immunotherapy that could selectively inhibit pathogenic immune pathways.