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

Significance A successful vaccine depends on productive T follicular helper (T FH ) and B-cell responses to elicit protective immunity. Vaccines are delivered as live-attenuated viruses, inactivated organisms, or protein subcomponents via different routes. In the context of protein immunization, we demonstrate that Tcf1 and Lef1 transcription factors play critical roles in suppressing excessive induction of CTLA4 and LAG3 coinhibitory receptors in T FH cells and, hence, preventing undue inhibition of B cells. This function is in contrast to the requirement for Tcf1 and Lef1 in induction of Bcl6 in T FH cells elicited by viral or bacterial infections. These findings highlight that the same protein factors could be utilized to regulate distinct aspects of T FH cell differentiation depending on vaccination routes and regimens.