STAT1 is required for Tfh lineage maintenance through regulation of IL-21 expression

Abstract

Abstract T follicular helper (Tfh) cells are a specialized subset of T helper cells necessary for germinal center reaction, affinity maturation, and the differentiation of germinal center B cells to antibody-producing plasma B cells and memory B cells. The differentiation of Tfh cells is a multistage, multifactorial process involving a variety of cytokines, surface molecules and transcription factors. While to date early signaling events for fate committed differentiation of Tfh cells are sufficiently studied, mechanisms allowing Tfh cells to maintain their commitment/programming are still unclear. Here we report that STAT1 deficiency in CD4+ T cells leads to diminished number of Tfh cells at day 7 and 14 days after antigen immunization, while at day 3–4, number of Tfh cell were comparable between STAT1-sufficient and STAT1-deficient mice, suggesting the role of STAT1 in Tfh lineage maintenance rather than in Tfh cell priming. Interestingly STAT 1 deficiency in both mouse and human Tfh cells leads to significant drop in IL-21 expression, while the expression of Tfh-specific genes such as Bcl6, CXCR5 and c-Maf was not affected. Functionally, STAT1 in cooperation with STAT3 triggers IL-21 production in Tfh cells by directly binding to and activation of the IL-21 gene locus. In addition, STAT1/STAT3 cooperation influences the expression of transcriptional factor Batf as well as determines Batf-driven IL-21 expression in Tfh cells. Our results thus indicate STAT1 dependent mechanism for IL-21 expression and Tfh lineage maturation and maintenance.