Trends in Immunology
ReviewSeries: Tissue-resident immune cellsTissue instruction for migration and retention of TRM cells
Introduction
Immunological memory provides the vertebrate host with a crucial means to protect against multiple infections by the same pathogen, and forms the basis of vaccines. The cardinal features of immunological memory are that it is specific to the pathogen, provides more immediate and stronger response to the pathogen, and is long lived. Over the past decade, the field of immunology has come to appreciate the existence and the importance of the memory T cells that reside in peripheral tissues. Various non-lymphoid organs are seeded by effector T cells (Teffs) during infection or immunization, where these cells differentiate and develop into memory T cells with distinct phenotype and function. The tissue microenvironment provides instructive signals for the Teffs to express molecules that enable long-term residency and survival. Importantly, once established, such tissue-resident memory T cells (TRMs) provide protective immunity against infectious microbial agents that enter through the local tissues 1, 2. Therefore, studying and understanding the biology of TRMs will provide important insights into the natural immunological mechanism of host protection at the site of pathogen entry, as well as being a basis for designing future vaccines against mucosal pathogens.
The differentiation pathway from naïve lymphocytes to TRMs is beginning to be understood. In the secondary lymphoid tissue, naïve T cells that are activated in response to infection undergo differentiation programs to become Teffs that are capable of migrating to the site of infection to clear the pathogen. The Teff population can be largely divided into short-lived effector cells (SLECs), whose primary role is to control infection, and memory precursor effector cells (MPECs), which give rise to long-lived memory T cells 3, 4. SLECs and MPECs are characterized by distinct cell surface expression of KLRG1hiIL-7Rαlow and KLRG1lowIL-7Rαhi, respectively. Both of these Teff populations exit the lymph nodes through the efferent lymph and enter the circulation. In the post-capillary venules near the site of infection, Teffs receive signals to slow down, adhere to the endothelium, and enter the tissue through transendothelial migration. Once inside the tissue, Teff populations migrate toward the infected cells along the chemokine gradient to kill infected cells [5]. Notably, while both KLRG1hi and KLRG1low Teffs enter the tissue during the acute phase of infection, only the latter give rise to the CD8 TRM population in the skin after the resolution of infection [6].
Recent studies have also revealed distinct tissue classes with different degree of access to Teff entry at steady state (Table 1). Some tissues, such as the intestinal epithelium and peritoneal cavity, are seeded by TRM precursors (Teffs) in the absence of local inflammation, while others, including the skin epidermis, vaginal epithelium, lung airways, salivary glands, and ganglia, require direct infection or inflammation to recruit TRM precursors and maintain TRMs [7]. Permissive tissues constitutively express homing molecules that enable Teffs to enter and establish residency within the tissue, while restrictive tissues require inflammatory cytokines and chemokines to render endothelial cells permissive to Teff migration. A well-known example of a permissive tissue-homing molecule is mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1), which is constitutively expressed by the endothelial cells of the intestinal mucosa. Curiously, α4β7, the homing receptor for MAdCAM-1, is upregulated on Teffs acutely around 4.5 days after infection, which permits access by Teffs to the intestinal epithelium [8]. While some TRMs reside in the epithelial layer in a seemingly random fashion in the absence of their cognate antigens, other types of TRM require a microenvironment that provides chemokine and antigenic stimuli. The latter type can be found within a recently reported structure, the memory lymphocyte clusters (MLCs) [9], located strategically close to the mucosal surface. Studies have also revealed that the superior protection provided by TRMs is based in part on their proximity to the invading pathogens but also on intrinsic and extrinsic factors that govern their immediate effector functions. In this review we discuss the role of the tissue microenvironment in supporting the recruitment, residency, and effector functions of TRMs. The main topics addressed include: (i) the homing receptors and chemokines that orchestrate each step of the migration of TRM precursors from the circulation into tissue; (ii) the retention signals provided by the surrounding cells that support the maintenance of CD8 TRMs and CD4 TRMs; (iii) a discussion of the MLC as a housing complex for TRMs; and (iv) the unique TRM features that enable efficient execution of their effector functions.
Section snippets
Rolling signals for TRM precursors
Lymphocyte migration into inflamed tissues occurs through sequential steps involving interaction between specific molecules expressed by lymphocytes and their counter-receptors (Box 1). The molecules that control each step of activated lymphocyte seeding of the TRM pool are being uncovered. Much of this understanding is based on a study of HSV-1 infection in mice and therefore may be different for other infections and immunizations. E-selectin ligand is expressed by most CD4 Teffs after
Chemokine activation of TRM precursors
The chemokines that are important in arresting rolling lymphocytes depend on the target tissue. It is well established that leukocyte stimulation by chemokines occurs through chemokines presented by heparan sulfate glycosaminoglycans, which present the chemokines on their apical and basolateral surfaces of the endothelial cells [12]. A recent provocative study challenged this view for Teffs. Using human umbilical vein endothelial cells (HUVECs), the study demonstrated that silencing of
Arresting signals for TRM precursors
The next step to becoming a resident cell involves chemokine-dependent activation of integrins, which enables the lymphocytes to arrest on the endothelial surface [12]. Gut-homing T cells express the integrin α4β7 [29], which mediates T-cell binding to MAdCAM-1 at steady state 30, 31. MAdCAM-1 is expressed by intestinal but not cutaneous vascular endothelium [32]. In tissues that are restricted from entry of Teffs in the absence of local inflammation, there is little constitutive expression of
Transendothelial migration of TRM precursors
The arrested lymphocytes must cross the endothelial cells and their associated cell types (pericytes and perivascular macrophages) to gain access to the tissue [12]. The process of transendothelial migration requires sequential and reciprocal signaling between the lymphocytes and endothelial cells involving platelet/endothelial cell adhesion molecule (PECAM)–PECAM (homophilic), CD99–CD99 (homophilic), junctional adhesion molecules (JAMs), integrins, and VE-cadherin [36] (Figure 1). Human CD4
Retention and survival signals for CD8 TRMs
Once inside the tissue, lymphocytes migrate toward the source of chemokines through sensing of the chemokine gradient. To remain resident in the tissue, lymphocytes are likely to respond to positive cues, probably via interaction with supportive structures such as the extracellular matrix and fibroreticular cells, and must also downregulate egress receptors to avoid exit cues. In addition to control of migration, memory T cells require growth factor for their survival. Recent studies have shed
Retention signals for CD4 TRMs
Although much less is understood regarding the signals for maintenance of CD4 TRMs, they appear similar to those for LP CD8 TRMs but distinct from those for epithelial CD8 TRMs, as discussed below. As with CD8 TRMs, CD4 TRM precursor (CD4 Teff) access is restricted in certain tissues (skin and vagina) and permissive in others (lung). CD4 memory T cells isolated from the lung of mice infected with influenza virus specifically home back to the lung after adoptive transfer, whereas those isolated
Memory lymphocyte clusters as hubs for TRM maintenance
After a local infection or immunization, memory lymphocytes formed within the parenchyma of the tissue are maintained in clusters comprising distinct cell types. Here we specifically focus on the MLC and not the clusters that mediate the induction of T cells during the primary immunization or infection 55, 56, 57. The MLCs are distinct from tertiary lymphoid organs (TLOs) in that MLCs do not have high endothelial venules (HEVs) and are therefore devoid of naïve lymphocytes, do not have direct
Effector phase of TRM control of pathogens
TRMs control invading pathogens more efficiently than circulating memory T cells. The enhanced ability of TRMs in antimicrobial function is based on their location and their cell-intrinsic and -extrinsic capabilities, as discussed further below. The location of TRMs with respect to the invading pathogen is likely to provide them with an advantage in responding more quickly than their circulating memory T cell counterparts. CD8 TRMs are localized within the epithelium where the viral infection
Concluding remarks
Effector T cells are programmed to proliferate, differentiate, and home to various lymphoid and non-lymphoid tissues to become memory T cells. An important part of the programming occurs after the effector T cells migrate and enter their destination site. Thus, T-cell memory can be considered to have specificity not only to the molecular details of the pathogen (through the recognition of epitopes via the antigen receptor) but also to the location of invasion (through the establishment of TRMs).
Acknowledgments
The authors are grateful to Haina Shin for her advice on the manuscript and Katharine Ng for preparing the illustrations. Funding sources include grants from National Institutes of Health R01, AI081884, AI054359, AI062428, AI064705, and AI102625 and funding from Women's Health Research at Yale and the AbbVie–Yale collaboration. A.I. is an investigator of the Howard Hughes Medical Institute.
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