Regulation of Tfh cell development through STAT1 signaling

Abstract

Abstract T follicular helper (Tfh) cells play a key role in providing help to B cells during germinal center (GC) reactions. The generation and function of Tfh cells is regulated by multiple checkpoints including their early priming stage in T zones and throughout the effector stage of differentiation in GCs. Signaling pathways activated downstream of cytokine and costimulatory receptors as well as consequent activation of subset-specific transcriptional factors are essential steps for Tfh cell generation. 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 signal transducer and activator of transcription 1 (STAT1) deficiency in CD4+ T cells leads to a diminished number of Tfh cells at day 7 and 14 days after antigen immunization, while at day 3–4, number of Tfh cells was comparable between STAT1-sufficient and STAT1 deficient mice, suggesting the role of STAT1 in Tfh lineage maintenance rather than in Tfh cell priming. In fact, in both mouse and human Tfh cells interleukin (IL)-21 mRNA and protein expression is dependent on the presence of STAT1. Functionally, STAT1 in cooperation with STAT3, Batf, and IRF4 triggers IL-21 production in Tfh cells by directly binding to and activation of the IL-21 gene locus. Moreover, utilizing gene knockout approach, we have determined that Batf is a crucial connector to form STAT1/STAT3/Batf/IRF4 active complex for triggering IL-21 transcription. Our results thus indicate functional contribution of STAT1 towards regulation of IL-21 expression and Tfh lineage maturation/maintenance.