Decoding Tissue-Residency: Programming and Potential of Frontline Memory T Cells

Abstract

Memory T-cell responses are partitioned between the blood, secondary lymphoid organs, and nonlymphoid tissues. Tissue-resident memory T (Trm) cells are a population of immune cells that remain permanently in tissues without recirculating in blood. These nonrecirculating cells serve as a principal node in the anamnestic response to invading pathogens and developing malignancies. Here, we contemplate how T-cell tissue residency is defined and shapes protective immunity in the steady state and in the context of disease. We review the properties and heterogeneity of Trm cells, highlight the critical roles these cells play in maintaining tissue homeostasis and eliciting immune pathology, and explore how they might be exploited to treat disease.

Figure 1.

Regulation of T-cell residency formation and persistence in peripheral tissues. Trm cell formation is controlled at multiple stages of T-cell homeostasis, activation, and differentiation. Naive CD8⁺ T cells can be preconditioned for T-cell residency potential by interacting with dendritic cells (DCs) that activate transforming growth factor β (TGF-β) in lymph nodes (LNs) prior to T-cell priming. Activated T cells migrate to the periphery where Trm differentiation occurs in situ following exposure to tissue-derived cytokines that can include TGF-β and interleukin 15 (IL-15). Full commitment to the T-cell residency fate is often associated with the up-regulation of molecules including CD69 and CD103 and down-regulation of factors that promote T-cell egress from tissues such as Klf2 and S1pr1. In addition, Trm cells acquire a unique transcriptional profile that may include up-regulation of residency-promoting factors such as Znf683, Runx3, and Bhlhe40. In the context of chronic infections or cancer where persistent antigen may be present, residency-associated molecules might also be dynamically regulated in recently activated or effector T cells that could eventually return to the circulation.

Figure 2.

Functions of Trm cells in infection, cancer, and autoimmune disorders. Upon restimulation, Trm cells can rapidly produce a variety of effector molecules with diverse immune functions, including interferon γ (IFN-γ), GzmB, tumor necrosis factor (TNF), interleukin (IL)-2, and IL-17. Many of the cytokines produced by Trm cells can recruit and activate downstream immune cells found either locally in the surrounding tissue or in the circulation, including B cells, natural killer (NK) cells, and circulating T cells. This “sense-and-alarm” function of Trm cells may combine with their capacity for direct effector function (e.g., via cell killing or direct functions of cytokines on abnormal cells), allowing them to provide superior protection against infection and cancer by comparison with circulating T cells or endowing them with the capacity to orchestrate autoimmunity.