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.