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.