Transcriptional regulation of IL-4 expression in T follicular helper cells (IRM15P.456)

Abstract

Abstract Apart from Th2 cells T follicular helper (Tfh) cells are a major class of IL-4 producing T cells, required for regulation of type 2 humoral immune responses. Although the transcriptional control of IL-4 in Th2 cells has been extensively investigated, the precise regulation mechanism(s) of IL-4 production in Tfh cells remains mainly unknown. In the current study, we found that the transcription factor Batf, a member of the AP-1/Jun family is essential for IL-4 expression in Tfh cells. Remarkably, Batf deficiency leads to decreased IL-4 production selectively in Tfh cells but not in conventional Th2 cells and subsequently to reduction in their pro-allergic pathogenicity. Batf in cooperation with Interferon regulatory factor (IRF)4 controls IL-4 production in Tfh cells by directly binding to and activation of the CNS2 region of the IL-4 locus. The transcription factors Stat3 and Stat6 also aid in Batf/IRF4 binding to the CNS2 locus thus playing a crucial role in Batf-mediated regulation of IL-4 in Tfh cells. We also found that enhanced expression of Batf in Tfh cells is largely dependent on IL-4/Stat6 signaling, indicating towards a positive feedback loop in controlling Batf-IL-4 expression in Tfh cells. Our results thus identify a novel and critical role of Batf in promoting the generation of pro-allergic IL-4 producing Tfh cells.