STAT4 and T-bet control follicular helper T cells development in viral infections [ATAC-seq]

Follicular helper T (Tfh) cells promote germinal center (GC) B cell survival and proliferation, and guide their differentiation and Ig isotype switching by delivering contact-dependent and soluble factors, including IL-21, IL-4, IL-9, and IFN-g. IL-21 and IFN-g are co-expressed by Tfh cells during acute and chronic infections, but transcriptional regulation of these cytokines in the GC is incompletely understood. We show that the Th1 transcriptional regulators T-bet and STAT4 are co-expressed with Bcl6 in Tfh cells following acute murine lymphocytic choriomeningitis virus infection, albeit with temporal decline in T-bet expression as the GC response evolved. T-bet was important for Tfh cell production of IFN-g, but not IL-21, and for the generation of a robust germinal center reaction. STAT4, phosphorylated in Tfh cells upon infection, was required for their expression of T-bet and Bcl6, and that of IFN-g and IL-21. These data indicate that T-bet is concomitantly expressed with Bcl6 in Tfh cells and is required alongside STAT4 phosphorylation to coordinate Tfh cell IL-21 and IFN-g production, and for promotion of the GC response following acute viral challenge. Each group consisted of 5 mice pooled together. Two replicates of each group were used for ATAC-seq. Two groups were studied: Wild-type and homozygous STAT4 knockout mice.