Tissue-resident memory T cells in tissue homeostasis, persistent infection, and cancer surveillance

A large proportion of memory T cells disseminated throughout the body are non-recirculating cells whose maintenance and function is regulated by tissue-specific environmental cues. These sessile cells are referred to as tissue-resident memory T (T_RM ) cells and similar populations of non-recirculating cells also exist among unconventional T cells and innate lymphocyte cells. The pool of T_RM cells is highly diverse with respect to anatomical positioning, phenotype, molecular regulation and effector function. Nevertheless, certain transcriptional programs are shared and appear as important unifying features for the overall population of T_RM cells and tissue-resident lymphocytes. It is now widely appreciated that T_RM cells are a critical component of our immune defense by acting as peripheral sentinels capable of rapidly mobilizing protective tissue immunity upon pathogen recognition. This function is of particular importance in anatomical sites that are not effectively surveilled by blood-borne memory T cells in absence of inflammation, such as neuronal tissues or epithelial compartments in skin and mucosae. Focusing on the well-characterized subtype of CD8⁺  CD69⁺  CD103⁺ T_RM cells, we will review current concepts on the generation, persistence and function of T_RM cells and will summarize commonly used tools to study these cells. Furthermore, we will discuss accumulating data that emphasize localized T_RM responses as an important determinant of tissue homeostasis and immune defense in the context of microbiota-immune interactions, persistent infections and cancer surveillance.