Stem-like tissue-resident memory T cells control functional heterogeneity and reactivation of T cell memory in the intestine

Tissue-resident memory T (T RM ) cells provide localized immunity against intracellular pathogens and cancer. Upon antigen reencounter, T RM cells differentiate into effector cells while also giving rise to another generation of memory cells. Here, we show that intestinal T RM cells that express the transcriptional regulators TCF1 or ID3 exhibit stem-like memory properties and are endowed with a superior capacity to regenerate effector and memory T cells after pathogen reencounter. Ablation of TCF1 using a T RM cell–specific mouse model resulted in impaired formation of intestinal T RM cells, altered their transcriptional heterogeneity, and increased their differentiation into tissue-confined and recirculating CX3CR1 + effector cells during recall. TGF-β and retinoic acid were required for formation and survival of TCF1- and ID3-expressing T RM cells and restrained their differentiation into CX3CR1 + effector cells during reinfection. Thus, stem-like cells control the quality and recall capacity of T RM cells, thereby contributing to anamnestic memory responses.