Antigen-Specific Hhexhigh CD4+ effectors as bona fide precursors of memory TFH cells to safeguard long-term humoral immunity [CUT&TAG]

However, the mechanism underlying memory TFH cell differentiation is largely unknown. Here, we show that a subset of antigen-specific CD4 effector cells highly expressing transcription factor Hhex (Hhexhigh ) functioned as the precursors (termed Hhexhigh precursors) for generating long-lived memory TFH cells.

Hhexhigh precursors exhibited circulation between blood and lymphoid tissue under homeostatic conditions in mice, and were largely committed to central memory (TCM)/effector memory (TEM) that were re-elicited TFH cells upon cognate antigen restimulation. Furthermore, we identified that Hhex positively regulated Cxcr5 and Gpx4 expression through binding their promoters associated with increased chromatin accessibility to specifically support memory TFH cell differentiation and maintenance.