Antigen‐presenting cell‐derived IL‐6 restricts the expression of GATA3 and IL‐4 by follicular helper T cells

Follicular helper T cells (Tfh) support high‐affinity Ab production by germinal center B cells through both membrane interactions and secretion of IL‐4 and ‐21, two major cytokines implicated in B‐cell survival and Ab class switch. Tfh‐2 cells recently emerged in humans as a strong IL‐4 producer Tfh cell subset implicated in both autoimmune and allergic diseases. Although the molecular mechanisms governing Tfh cell differentiation from naive T cells have been widely described, much less is known about the regulation of cytokine secretion by mouse Tfh‐2 cells. The purpose of our study was to evaluate the role of dendritic cell–derived IL‐6 in fine‐tuning cytokine secretion by Tfh cells. Our results demonstrate that priming of Th cells by IL‐6‐deficient antigen‐presenting dendritic cells preferentially leads to accumulation of a subset of Tfh cells characterized by high expression of GATA3 and IL‐4, associated with reduced production of IL‐21. STAT3‐deficient Tfh cells also overexpress GATA3, suggesting that early IL‐6/STAT3 signaling during Tfh cell development inhibits the expression of a set of genes associated with the Th2 differentiation program. Overall, our data indicate that IL‐6/STAT3 signaling restrains the expression of Th2‐like genes in Tfh cells, thus contributing to the control of IgE secretion in vivo. IL‐6/STAT3 signaling modulates the cytokine and transcription factor pattern of Tfh cells and controls IgE secretion in vivo.