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

[BACKGROUND] Tissue-resident memory T (T) 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 cells have unique homing and functional characteristics that are shaped by the tissue microenvironment. In the gut, T 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 (iT) 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 cells for intestinal health and disease management. KEY SCIENTIFIC CONCEPTS OF REVIEW: iT 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 cells play a dual role, contributing to both inflammation and tissue repair, whereas in CRC, specific subsets of iT cells (e.g., CD8 CD103 CD39) are associated with enhanced antitumor immunity. Aging impacts iT 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 cells provide avenues for targeted therapies in intestinal diseases, cancer immunotherapy, and interventions to delay intestinal aging.