T _H 17 cells require ongoing classic IL-6 receptor signaling to retain transcriptional and functional identity

Abstract

Acting in concert with TGF-β, interleukin-6 (IL-6) signaling induces T helper 17 (T_H17) cell development by programming T_H17-related genes via signal transducers and activators of transcription 3 (STAT3). A role for IL-6 signaling beyond the inductive phase of T_H17 cell development has not been defined because IL-23 signaling downstream of T_H17 cell induction also activates STAT3 and is thought responsible for T_H17 cell maintenance. Here, we find that IL-6 signaling is required for both induction and maintenance of mouse T_H17 cells; IL-6Rα-deficient T_H17 cells rapidly lost their T_H17 phenotype and did not cause disease in two models of colitis. Cotransfer of wild-type T_H17 cells with IL-6Rα-deficient T_H17 cells induced colitis but was unable to rescue phenotype loss of the latter. High IL-6 expression in the colon promoted classic, or cis, rather than transreceptor signaling that was required for maintenance of T_H17 cells. Thus, ongoing classic IL-6 signaling underpins the T_H17 program and is required for T_H17 cell maintenance and function.