STAT3 but not STAT4 is critical for γδT17 cell responses and skin inflammation.

The transcription factors STAT3 and STAT4 are essential for lymphocyte differentiation and function. Interleukin (IL)-17 producing γδ T (γδT17) cells are innate lymphocytes important for anti-bacterial and inflammatory responses at barrier surfaces. Herein, we examine the role of STAT3 and STAT4 in regulating the homeostasis, activation, and pathogenicity of γδT17 cells. We show that STAT3 sustains γδT17 numbers in the skin but not in the lymph nodes, while STAT4 deficiency does not affect their homeostasis. Similarly, STAT3 but not STAT4 is essential for IL-23-induced IL-22 production by γδT17 cells. Concomitantly, mice lacking STAT3 expression in γδT17 cells develop significantly reduced psoriasis-like inflammation. STAT3-deficient γδT17 cells fail to expand and to upregulate IL-17A, IL-17F, and IL-22 in response to psoriatic stimuli. Although STAT4-deficient animals develop psoriasis-like disease, γδT17 cells in these mice are defective in IL-17F production. Collectively, our data demonstrate for the first time a critical role for STAT3 in orchestrating the homeostasis and pathogenicity of γδT17 cells and provide evidence for the requirement of STAT4 for optimal cytokine responses during inflammation.