T_FH cells depend on Tcf1-intrinsic HDAC activity to suppress CTLA4 and guard B-cell help function

Precise regulation of coinhibitory receptors is essential for maintaining immune tolerance without interfering with protective immunity, yet the mechanism underlying such a balanced act remains poorly understood. In response to protein immunization, T follicular helper (T_FH) cells lacking Tcf1 and Lef1 transcription factors were phenotypically normal but failed to promote germinal center formation and antibody production. Transcriptomic profiling revealed that Tcf1/Lef1-deficient T_FH cells aberrantly up-regulated CTLA4 and LAG3 expression, and treatment with anti-CTLA4 alone or combined with anti-LAG3 substantially rectified B-cell help defects by Tcf1/Lef1-deficient T_FH cells. Mechanistically, Tcf1 and Lef1 restrain chromatin accessibility at the Ctla4 and Lag3 loci. Groucho/Tle corepressors, which are known to cooperate with Tcf/Lef factors, were essential for T_FH cell expansion but dispensable for repressing coinhibitory receptors. In contrast, mutating key amino acids in histone deacetylase (HDAC) domain in Tcf1 resulted in CTLA4 derepression in T_FH cells. These findings demonstrate that Tcf1-instrinsic HDAC activity is necessary for preventing excessive CTLA4 induction in protein immunization-elicited T_FH cells and hence guarding their B-cell help function.