Tcf1 preprograms the mobilization of glycolysis in central memory CD8⁺ T cells during recall responses

The mechanisms underlying the heightened protection mediated by central memory CD8⁺ T (T_CM) cells remain unclear. Here we show that the transcription factor Tcf1 was required in resting T_CM cells to generate secondary effector CD8⁺ T cells and to clear pathogens during recall responses. Recall stimulation of CD8⁺ T_CM cells caused extensive reprogramming of the transcriptome and chromatin accessibility, leading to rapid induction of glycolytic enzymes, cell cycle regulators and transcriptional regulators, including Id3. This cluster of genes did not require Tcf1 in resting CD8⁺ T_CM cells, but depended on Tcf1 for optimal induction and chromatin opening in recall-stimulated CD8⁺ T_CM cells. Tcf1 bound extensively to these recall-induced gene loci in resting CD8⁺ T_CM cells and mediated chromatin interactions that positioned these genes in architectural proximity with poised enhancers. Thus, Tcf1 preprogramed a transcriptional program that supported the bioenergetic and proliferative needs of CD8⁺ T_CM cells in case of a secondary challenge.