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Differentiation of T follicular helper (T FH ) cells is regulated by a complex transcriptional network, with mutually antagonistic Bcl6-Blimp1 as a core regulatory axis. It is well established that Tcf1 acts upstream of Bcl6 for its optimal induction to program T FH cell differentiation. In this study, we show that whereas genetic ablation of Tcf1 in mice greatly diminished T FH cells in response to viral infection, compound deletion of Blimp1 with Tcf1 restored T FH cell frequency, numbers, and generation of germinal center B cells. Aberrant upregulation of T-bet and Id2 in Tcf1-deficient T FH cells was also largely rectified by ablating Blimp1. Tcf1 chromatin immunoprecipitation sequencing in T FH cells identified two strong Tcf1 binding sites in the Blimp1 gene at a 24-kb upstream and an intron-3 element. Deletion of the intron-3 element, but not the 24-kb upstream element, compromised production of T FH cells. Our data demonstrate that Tcf1-mediated Blimp1 repression is functionally critical for safeguarding T FH cell differentiation.

Cutting Edge: Tcf1 Instructs T Follicular Helper Cell Differentiation by Repressing Blimp1 in Response to Acute Viral Infection