Hallmarks of Tissue-Resident Lymphocytes

Abstract

Although they are classically viewed as continuously recirculating through the lymphoid organs and blood, lymphocytes also establish residency in non-lymphoid tissues, most prominently at barrier sites, including the mucosal surfaces and skin. These specialized tissue-resident lymphocyte subsets span the innate-adaptive continuum and include innate lymphoid cells (ILCs), unconventional T cells (e.g., NKT, MAIT, γδ T cells, and CD8αα(+) IELs), and tissue-resident memory T (T(RM)) cells. Although these diverse cell types differ in the particulars of their biology, they nonetheless exhibit important shared features, including a role in the preservation of tissue integrity and function during homeostasis, infection, and non-infectious perturbations. In this Review, we discuss the hallmarks of tissue-resident innate, innate-like, and adaptive lymphocytes, as well as their potential functions in non-lymphoid organs.

Figure 1. Tissue-Resident versus Recirculating Lymphocytes and Their Functions

Tissue-resident lymphocytes are principally found in barrier tissues, where they serve as sentinels and frontline defenders of tissue integrity in response to infection and non-infectious insults. Recirculating lymphocyte subsets actively survey the body for similar perturbations of homeostasis by patrolling the lymphatic and blood circulatory systems and associated secondary lymphoid organs (lymph nodes and spleen). While some lymphocyte subsets, most prominently ILCs, display almost exclusively tissue-resident behavior, circulating counterparts to other adaptive lymphocyte subsets, including NK, NKT, MAIT, γδ T, and αβ T cells can also be found in peripheral blood, albeit at lower frequencies.

Figure 2. Modes of Sensing and Provision of Effector Function by Tissue-Resident Innate, Innate-like and Adaptive Lymphocytes

Note that γδTCRs can be activated by a variety of antigens with or without presenting molecules; only one mode of γδTCR activation is shown. Also, both CD4+ and CD8+ T_RM cells have been described, although only the former is depicted.

Figure 3. Amplification of Immune Responses by Tissue-Resident Lymphocytes

(A) Feed-forward loop in the early type 2 response to intestinal helminth infection. Helminth infection triggers release of IL-33 from dying epithelial cells and IL-25 from chemosensory tuft cells. These cytokines activate ILC2s to produce IL-13, which acts on the stem cell compartment to induce goblet and tuft cell hyperplasia. (B) Triggered by cognate antigen, CD8+ T_RM cells release interferon-gamma, which initiates a tissue-wide state of alarm and recruits circulating memory cells. (C) NKT cells rapidly produce cytokines and upregulate CD40L after being activated by Kupffer cells presenting CD1d-bound glycolipids derived from bloodborne bacterial pathogens.