Small intestine and colon tissue-resident memory CD8⁺ T cells exhibit molecular heterogeneity and differential dependence on Eomes

Tissue-resident memory CD8⁺ T (T_RM) cells are a subset of memory T cells that play a critical role in limiting early pathogen spread and controlling infection. T_RM cells exhibit differences across tissues, but their potential heterogeneity among distinct anatomic compartments within the small intestine and colon has not been well recognized. Here, by analyzing T_RM cells from the lamina propria and epithelial compartments of the small intestine and colon, we showed that intestinal T_RM cells exhibited distinctive patterns of cytokine and granzyme expression along with substantial transcriptional, epigenetic, and functional heterogeneity. The T-box transcription factor Eomes, which represses T_RM cell formation in some tissues, exhibited unexpected context-specific regulatory roles in supporting the maintenance of established T_RM cells in the small intestine, but not in the colon. Taken together, these data provide previously unappreciated insights into the heterogeneity and differential requirements for the formation vs. maintenance of intestinal T_RM cells.