Cutting Edge: STAT1 Is Required for IL-6–Mediated Bcl6 Induction for Early Follicular Helper Cell Differentiation

Bcl6 is required for CD4 T cell differentiation into T follicular helper cells (Tfh). In this study, we examined the role of IL-6 in early processes of in vivo Tfh differentiation, because the timing and mechanism of action of IL-6 in Tfh differentiation have been controversial in vivo. We found that early Bcl6(+)CXCR5(+) Tfh differentiation was severely impaired in the absence of IL-6; however, STAT3 deficiency failed to recapitulate that defect. IL-6R signaling activates the transcription factor STAT1 specifically in CD4 T cells. Strikingly, we found that STAT1 activity was required for Bcl6 induction and early Tfh differentiation in vivo. IL-6 mediated STAT3 activation is important for downregulation of IL-2Rα to limit Th1 cell differentiation in an acute viral infection. Thus, IL-6 signaling is a major early inducer of the Tfh differentiation program unexpectedly mediated by both STAT3 and STAT1 transcription factors.