Insights into phenotypic and functional CD8⁺ T_RM heterogeneity

Cytotoxic CD8⁺ T cells recognize and eliminate infected or cancerous cells. A subset of CD8⁺ memory T cells called tissue-resident memory T cells (T_RM ) resides in peripheral tissues, monitors the periphery for pathogen invasion, and offers a rapid and potent first line of defense at potential sites of re-infection. T_RM cells are found in almost all tissues and are transcriptionally and epigenetically distinct from circulating memory populations, which shows their ability to acclimate to the tissue environment to allow for long-term survival. Recent work and the broader availability of single-cell profiling have highlighted T_RM heterogeneity among different tissues, as well as identified specialized subsets within individual tissues, that are time and infection dependent. T_RM cell phenotypic and transcriptional heterogeneity has implications for understanding T_RM function and longevity. This review aims to summarize and discuss the latest findings on CD8⁺ T_RM heterogeneity using single-cell molecular profiling and explore the potential implications for immune protection and the design of immune therapies.