Abstract
Tissue-resident memory T (TRM) cells mediate potent local innate and adaptive immune responses and provide long-lasting protective immunity. TRM 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 TRM 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 TRM cell compartment. Here, we review the phenotypic and functional heterogeneity of CD8+ TRM cells at different tissue sites and the molecular determinants defining CD8+ TRM cell subsets. We further discuss the possibilities of targeting the unique cell surface molecules, cytokine and chemokine receptors, transcription factors, and metabolic features of TRM cells for therapeutic purposes. Their crucial role in immune protection and their location at the frontlines of the immune defense make TRM cells attractive therapeutic targets. A better understanding of the possibilities to selectively modulate TRM cell populations may thus improve vaccination and immunotherapeutic strategies employing these potent immune cells.
Highlights
CD8+ T cells play a crucial role in immune protection against pathogens and cancer [1].Upon antigen recognition following vaccination or infection, naïve antigen-specific CD8+T cells clonally expand and differentiate into effector cell populations
Targeting the inhibitory receptor NKG2A may be of interest, since this molecule is expressed on tumorinfiltrating NKG2A+ CD8+ TRM cells and the blockade of NKG2A potentiates CD8+ T cell immunity when combined with cancer vaccines and PD-1 blockade [99,100]
CD8+ TRM cells arising at different sites and responding to different infections are characterized by diverse phenotypes
Summary
CD8+ T cells play a crucial role in immune protection against pathogens and cancer [1]. Central memory T (TCM ) cells are characterized by expression of the lymph node homing molecules CD62L and CCR7, which enable them to patrol secondary lymphoid organs, whereas effector memory T (TEM ) cells lack these homing molecules and circulate throughout the body [2]. In contrast to their circulating counterparts, TRM cell populations localize to peripheral tissues and lymphoid organs, where they reside with minimal egress [3,4,5]. TRM cells rapidly release effector molecules, such as interferon-γ (IFN-γ), tumor necrosis factor (TNF), and granzyme B; initiate proliferation; and induce recruitment of other immune cells to the site of challenge [7,8]. We review the heterogeneous phenotypes and functions of CD8+ TRM cells and how their unique characteristics, including cell surfaces molecules, cytokine and chemokine receptors, transcription factors, and metabolic features, can be targeted to improve immunotherapies
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