Memory T cell formation and phenotype varies across intestinal compartments

Numerous studies have shown that tissue-resident memory T (T_RM) cells form in the intestine following pathogen clearance. However, most knowledge of intestinal T_RM cells has derived from analyses restricted to the small intestine (SI). In contrast, less is known about T_RM cell formation in the large intestine (LI). Here, we compared the abundance and phenotype of memory T cells across intestinal compartments. Using mouse models of infection, we observed that fewer memory T cells formed in the LI compared to the SI. Moreover, we found that T cells in the epithelium and lamina propria of the LI colon and caecum were phenotypically distinct from SI counterparts, comprising Ly6C-expressing CD8⁺ T_RM cells with a distinct cytokine and granzyme profile. Using both loss- and gain-of-function approaches, we identified site-specific TGF-β dependencies, whereby Ly6C⁺CD103^- T_RM cells developed independently of TGF-β in both the SI and LI. In contrast, augmenting TGF-β signalling preferentially expanded Ly6C^-T_RMpopulations in the LI but not the SI, indicating that TGF-β signalling drives T_RMcell heterogeneity between these compartments. Together, these findings underscore how regional differences in T_RM cell responsiveness to local cues shape their development, phenotype, and function along the gastrointestinal tract.