Insights into phenotypic and functional CD8⁺ T_RM heterogeneity

Abstract

Summary Cytotoxic CD8+ T cells recognize and eliminate infected or cancerous cells. A subset of CD8+ memory T cells called tissue‐resident memory T cells (TRM) 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. TRM 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 TRM heterogeneity among different tissues, as well as identified specialized subsets within individual tissues, that are time and infection dependent. TRM cell phenotypic and transcriptional heterogeneity has implications for understanding TRM function and longevity. This review aims to summarize and discuss the latest findings on CD8+ TRM heterogeneity using single‐cell molecular profiling and explore the potential implications for immune protection and the design of immune therapies.

The diverse landscape of memory T‐cell heterogeneity

“…Defining memory T‐cell heterogeneity in terms of circulating and tissue resident subsets required elucidating the transcriptional changes involved in subset delineation. Ananda Goldrath provides a comprehensive overview of the key advances in defining the transcription factors which delineate T RM from circulating memory subsets, including those identified by her group and others 12 . The Goldrath review further describes how T RM in specific sites exhibit tissue adaptations, and how they mediate secondary responses.…”

Protective function and differentiation cues of brain-resident CD8+ T cells during immune surveillance of chronic latentToxoplasma gondiiinfection

“…IFN-γ and granzyme B), or into memory precursor cells (MPC) (Belz and Kallies, 2010). MPC can give rise to 3 types of memory cells: (i) central memory cells (Tcm) that have stem-like properties and remain mostly within lymphoid organs, where they are poised for being recalled, (ii) effector memory cells (Tem) that navigate between peripheral tissues and lymphoid organs, and are equipped to quickly produce cytokines and cytotoxic factors upon restimulation, (iii) resident memory cells (Trm) that durably station within non-lymphoid tissues, including the central nervous system (CNS), where they provide local protective immunity against re-infection (Gebhardt et al, 2009; Heeg and Goldrath, 2023; Steinert et al, 2015; van Gisbergen et al, 2021).…”

“…Although the requirements are expected to differ according to the tissue microenvironment (Heeg and Goldrath, 2023), several general mechanisms underlie the differentiation and maintenance of CD8+ Trm across tissues. They include local antigen recognition and TCR signal strength (Abdelbary et al, 2023; Low et al, 2020; Maru et al, 2017; Sanecka et al, 2018), engagement of costimulatory receptors such as ICOS (Peng et al, 2022), signaling by cytokines such as type I IFN and IL-12 (Bergsbaken et al, 2017), IL-15 (Mackay et al, 2015), TGF-β (Ferreira et al, 2020; Mackay et al, 2015; Mani et al, 2019) and IL-21 (Ren et al, 2020; Tkachev et al, 2021), the latter illustrating the key contribution of CD4+ T cell help (Frieser et al, 2022; Son et al, 2021; Vincenti et al, 2022) in optimal CD8+ Trm differentiation.…”

Epithelial organoid supports resident memory CD8 T cell differentiation

“…Their duties, however, are compartmentalized, with distinct subsets of memory CD8 T cells performing surveillance responsibilities depending on their anatomic location. Specifically, circulating memory CD8 T cells, which encompass both central memory (TCM) and effector memory CD8 T cells (TEM), continuously patrol the bloodstream and secondary lymphoid organs (SLOs) such as the spleen and lymph nodes as well as non-lymphoid tissues (NLTs) 1–3 . Resident memory CD8 T cells (TRM), by contrast, are stationed within specific tissues and rarely recirculate through blood or lymphatics.…”