The mechanisms underlying heightened protection by CD8+ central memory T (Tcm) cells remain unclear. Here we show intact Tcf1 expression in resting Tcm cells is required for generating secondary effector cells and pathogen clearance during recall responses. Recall stimulation of Tcm cells causes extensive reprogramming of transcriptome and chromatin accessibility, leading to rapid induction of glycolytic enzymes, cell cycle regulators and transcriptional regulators including Id3. This cluster of genes does not require Tcf1 for expression in resting Tcm cells, but depends on Tcf1 for optimal induction and chromatin opening in recall-stimulated Tcm cells. Mechanistically, Tcf1 binds extensively to these recall-induced gene loci in resting Tcm cells, and mediates chromatin interactions that position these genes in architectural proximity with the ‘would-be’ enhancers. We propose the concept that Tcf1 preprograms the responsiveness of Tcm cells for mobilizing a transcriptional program that supports bioenergetic and proliferative needs in response to secondary challenge.

Pubmed link/accession of the paper PMID 35190717
RNA-seq, CUT&RUN-seq and HiC-seq are deposited in GEO under the accession number GSE177064

UCSC genome browser view of all the processed data can be found here. Trackhub file can be found here

TCF1 peaks in WT Rest
WT prepotent chrAcc sites (A1looseB4)

TCF1 signal in WT Rest
ATAC signal in WT Rest
ATAC signal in WT Stim
ATAC signal in Tcf1ko Rest
ATAC signal in Tcf1ko Stim