Intestinal tissue-resident memory T cells: Characteristics, spatial heterogeneity, age-related dynamics, and roles in disease regulation

Abstract

Background

Tissue-resident memory T (T_RM) cells are a distinct subset of memory T cells that persist in non-lymphoid tissues, providing localized and rapid immune responses to infection and malignancy. Unlike circulating memory T cells, T_RM cells have unique homing and functional characteristics that are shaped by the tissue microenvironment. In the gut, T_RM cells play a pivotal role in maintaining mucosal immunity, exhibiting phenotypic and functional heterogeneity in different intestinal compartments and in response to aging and pathological conditions.

Aim of review

This review aims to systematically examine the definition, spatial heterogeneity and functional roles of intestinal T_RM (iT_RM) cells. It highlights their contributions to physiological immunity, their involvement in pathological processes such as inflammatory bowel disease (IBD) and colorectal cancer (CRC), and their age-related dynamics. The review also explores emerging therapeutic implications of modulating iT_RM cells for intestinal health and disease management.

Key scientific concepts of review

iT_RM cells are defined by surface markers like CD69 and CD103, transcriptional regulators such as Hobit, Runx3, Blimp-1, as well as cytokine signals including TGF-β, IFN-β, IL-12. They exhibit spatial and functional heterogeneity across intestinal layers (epithelium versus lamina propria) and regions (small intestine versus colon). In IBD, iT_RM cells play a dual role, contributing to both inflammation and tissue repair, whereas in CRC, specific subsets of iT_RM cells (e.g., CD8⁺ CD103⁺ CD39⁺) are associated with enhanced antitumor immunity. Aging impacts iT_RM functionality, with shifts in the CD4⁺/CD8⁺ ratio and reduced cytokine production in elderly individuals. Insights into the metabolic, transcriptional, and environmental regulation of iT_RM cells provide avenues for targeted therapies in intestinal diseases, cancer immunotherapy, and interventions to delay intestinal aging.