Functional Heterogeneity and Therapeutic Targeting of Tissue-Resident Memory T Cells

Tissue-resident memory T (T_RM) cells mediate potent local innate and adaptive immune responses and provide long-lasting protective immunity. T_RM cells localize to many different tissues, including barrier tissues, and play a crucial role in protection against infectious and malignant disease. The formation and maintenance of T_RM cells are influenced by numerous factors, including inflammation, antigen triggering, and tissue-specific cues. Emerging evidence suggests that these signals also contribute to heterogeneity within the T_RM cell compartment. Here, we review the phenotypic and functional heterogeneity of CD8⁺ T_RM cells at different tissue sites and the molecular determinants defining CD8⁺ T_RM cell subsets. We further discuss the possibilities of targeting the unique cell surface molecules, cytokine and chemokine receptors, transcription factors, and metabolic features of T_RM cells for therapeutic purposes. Their crucial role in immune protection and their location at the frontlines of the immune defense make T_RM cells attractive therapeutic targets. A better understanding of the possibilities to selectively modulate T_RM cell populations may thus improve vaccination and immunotherapeutic strategies employing these potent immune cells.