Edited by: Weiguo Cui, Bloodcenter of Wisconsin, United States
Reviewed by: Vandana Kalia, School of Medicine, University of Washington, United States; Brian S. Sheridan, Stony Brook University, United States
This article was submitted to Immunological Memory, a section of the journal Frontiers in Immunology
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Tissue-resident-memory CD8+ T cells (TRM) have been described as a non-circulating memory T cell subset that persists at sites of previous infection. While TRM in all non-lymphoid organs probably share a core signature differentiation pathway, certain aspects of their maintenance and effector functions may vary. It is well-established that TRM provide long-lived protective immunity through immediate effector function and accelerated recruitment of circulating immune cells. Besides immune defense against pathogens, other immunological roles of TRM are less well-studied. Likewise, evidence of a putative detrimental role of TRM for inflammatory diseases is only beginning to emerge. In this review, we discuss the protective and harmful role of TRM in organ-specific immunity and immunopathology as well as prospective implications for immunomodulatory therapy.
During an infection, our immune defense operates in a sensitive balance in which the eradication of an invading pathogen should take place efficiently with the least possible damage to the body's own structures. For this, different subsets of immune cells have evolved, which form several lines of defense and are equipped with different functional specializations. Various leukocyte subsets—from broadly acting innate immune cells to antigen-specific and specialized lymphocytes—act together to constitute a joint defense reaction against infectious intruders. CD8+ (so-called cytotoxic) T lymphocytes are essential executors of the adaptive immune system and are particularly specialized in eliminating aberrant cells that are either infected with an intracellular pathogen or of tumorous nature. Regional and functional specialization can also be observed among CD8+ T cells, especially among memory T cells that provide long-term protection against reinfection with a previously encountered pathogen (
The principal hallmark of bona fide TRM is their long-term persistence in non-lymphoid tissues (NLT) as a stable memory T cell pool independent of input from circulating T cells. TRM are often identified by a combination of surrogate markers (see Table
Frequently used TRM markers in mice and humans.
CD69 | Almost all | Antagonisation of S1P1-mediated tissue egress | ( |
( |
CD103 | Subset |
Epithelial location via binding to E-Cadherin | ( |
( |
CD44 | All | Binding to hyaluronic acid | ( |
|
Bcl-2 | Subset | Longevity | ( |
( |
CD49a | Subset | Binding to Collagen and Laminin, specialization of effector function | ( |
( |
CD101 | Subset | Inhibition of T cell activation and proliferation | ( |
( |
GrB | All | Cytotoxicity | ( |
( |
CD127 | Subset | Homeostatic proliferation | ( |
( |
S1P1low | All | Low sensitivity to tissue egress signals | ( |
( |
S1P5low | All | Low sensitivity to tissue egress signals | ( |
|
CD62L low | All | Low sensitivity to tissue egress signals | ( |
( |
Ccr7low | All | Low sensitivity to tissue egress signals | ( |
( |
CX3CR1low | Subset | Low sensitivity to tissue egress signals | ( |
( |
KLRG1low | All | High memory potential | ( |
In humans, TRM and TRM-like cells are mostly identified in a descriptive manner based on the homology with mouse TRM (
TRM mostly arise from CD127(IL7Rα)+KLRG1- memory precursor cells (
The gene expression program of TRM generated in different tissues is largely overlapping (
Multiple factors influence TRM functionality.
One of the major incongruities of TRM differentiation in different organs is the dependency on local antigen expression. While TRM in the gut, skin and some mucosae can be generated and maintained independently of local antigen presentation (
TRM heterogeneity is particularly evident with regard to their expression of adhesion molecules. TRM in different organs (and even further, different subsets of TRM) show sometimes combined, sometimes exclusive expression of adhesion molecules such as CD103 (IntegrinαE), CD49a (Integrinα1β1), LFA-1 (IntegrinαLβ2), and E-Cadherin (
Cytokine redundancy (the common use of receptors and receptor subunits by different cytokines) and pleiotropy (multiple different functions exerted by one cytokine) are possible explanations for some of the observed variations in the dependency of TRM generation on cytokines in different experimental contexts. Interestingly, resting non-activated T cells share a common receptor (CD122/γc) for IL-2 and IL-15. It seems therefore likely that in conditions in which TRM precursors are exposed to e.g., high levels of IL-2 during the acute inflammatory response, IL-15 signaling becomes redundant for TRM generation. As mentioned above, both IL-7 and IL-15 can mediate pro-survival as well as homeostatic proliferation, and a certain functional redundancy might occur between these two cytokines, depending upon which receptors predominate on TRM or their precursors and which cytokine is available in the tissue niche occupied by TRM. Consistent with this idea, IL-15 dependency of TRM varies considerably between different organs and might be differentially required for TRM differentiation, survival and/ or homeostatic proliferation (
During their differentiation and long-term maintenance, TRM have to adapt to the metabolic environment of their tissue of residence. In most NLT, nutrients such as glucose and certain amino are more limited than in the circulation, and invading T cells need to adapt their metabolic processes to match their energy demands in this environment (
Despite providing the energy for T cell expansion and survival, the metabolic environment also dictates T cell differentiation and effector function (
Altogether, it seems likely that the combination of antigen load, inflammatory signals and nutrients in a tissue-specific niche creates a specific environmental context for TRM differentiation and maintenance (Figure
TRM serve as a front-line defense against viral re-infection in various tissues. Due to their unique positioning, often directly at barrier surfaces, they can rapidly detect invading pathogens and provide immediate immune function. In comparison, immune surveillance by circulating memory T cells is slower and often allows virus spread for several days before sufficient recruitment, local expansion, and differentiation of peripheral memory T cells takes place to confine and successfully combat infection (
Upon re-encounter of their cognate antigen, TRM employ two main paths to assure protection against the recurring pathogen. Firstly, they instantly provide highly potent cytotoxic effector functions that can eliminate the initially infected cells (barrier immunity) (
The protective capacity of TRM makes their generation a new objective for the development of vaccines. Indeed, skin vaccination and scarification during small pox vaccination that has now been associated with the generation of TRM has been shown to provide superior protective immunity than hypodermal injection (
Chronic inflammation results from repeated or continuous immune cell activation by recurrent or persisting antigens. Such responses are desirable to control latent-reactivating or persistent infections and to eliminate neoplastic cells. However, aberrant inflammation caused by environmental or self-antigens carries the risk of developing chronic inflammatory diseases, such as allergies and autoimmune diseases (AD). Indeed, TRM have been detected in several human inflammatory diseases (
TRM in human chronic inflammatory diseases.
Allergic contact dermatitis | CD3+ | ( |
DED | CCR7– CD45RO+/– CD69+ CD103+/– | ( |
Chronic rhinosinusitis | CD69+ S1P1– | ( |
FDE | CD69+ GrB+; CD45RA+ CD62L–CCR7– CD103+ | ( |
Psoriaris | CD103+; CD103+/– CD45RO+; CD103+ CD49a+ GrB+ | ( |
Systemic sclerosis | CD69+ CD103+/– | ( |
Type I diabetes | CD69+ CD103+; CD69+ CD103+/– | ( |
Multiple sclerosis | CD69+ CD103+/– GrB+/– S1P1– | ( |
HIV-1 | CD69+ CD103+/– S1P1– | ( |
HBV | CD69+ CD103+/–; CD69+ CD103+/– GrB+/– | ( |
HCV | CD69+ CD103+/– GrB+/– | ( |
Chronic pancreatitis | CD103+ | ( |
Rasmussen's encephalitis | CD103+ | ( |
HSV-2 | CD69+ CD103+/– | ( |
EBV | CD103+ | ( |
Breast cancer | CD69+ CD103+ GrB+ | ( |
Lung cancer | CD62L– CD69+ CD103+; CCR7– CD62L– CD69+ CD103+ CD49a+ S1P1– | ( |
Ovarian cancer | CD103+/– | ( |
Colorectal cancer | CD69+ CD103+/– CD49a+/– | ( |
One of the earliest reports on resident T cell responses came from latently-infected sensory ganglia, in which HSV reactivation was controlled by a non-circulating T cell population (
So far, we understand very little about how and whether functional TRM can be generated in conditions in which their cognate antigen is continuously present. Chronic high levels of antigen in some persistent infections, such as Lymphocytic choriomeningitis virus (LCMV) clone 13 or latent CMV, seem to hamper
Tumors can be a source of neo-antigens stimulating anti-tumor CD8+ T cell responses (
Tumor cells rely heavily on the uptake and metabolism of glucose and other nutrients, resulting in a metabolically-deprived tumor microenvironment (TME) (
It remains unknown, how tumor-associated TRM are generated. Analogous to persistent infections (
T cells specific for self-antigens or environmental antigens are considered active drivers of diverse allergic reactions such as food and drug allergies, asthma, and diabetes, as well as autoimmune diseases such as psoriasis, inflammatory bowel disease, and multiple sclerosis (MS). In the past, these diseases were considered to be driven by effector or effector memory T cells that infiltrate the affected organ, however, several lines of evidence suggest that some of these chronic inflammatory diseases or some disease stages are instead predominantly driven by resident immune cells (
One hallmark of allergic exacerbations is the short time frame (24–48 h) after exposure to the environmental trigger, in which exacerbations occur as is observed in FDE, a T cell-driven allergic local cutaneous reaction to certain administered drugs (
Allergen- or self-reactive T cell responses are usually considered to be elicited by preceding sensitizing events, which are hypothesized to occur in two main ways. Sequence similarities between a pathogen and an allergen- or self-antigen (also called molecular mimicry) can elicit pathogen-specific T cells that may cross-react to allergens or self-antigen upon future exposure (
Altogether, this supports the idea that pathogen-specific TRM generated during an infection could trigger and/or drive chronic inflammatory diseases. A possible connection between TRM and chronic inflammation could also provide a mechanistic explanation for the observed epidemiological association of infections and the development or exacerbation of allergic and autoimmune diseases (
Immunoregulatory mechanisms are in place to prevent extensive TRM accumulation in some organs or their over-activation. TRM generation is intimately linked to TGF-β (
Vaccine strategies inducing TRM against recurring infections are promising approaches to improve immunological protection. Equally, tumor-specific TRM might help to eradicate aberrant tumor cells from the body and enforce a localization of this response, thereby minimizing systemic side effects. However, several challenges have to be overcome to realize these goals, which are firstly of a technical nature. TRM generation cannot be monitored in peripheral blood and therefore requires the taking of biopsies from target organs, which might not always be easily performed. Further, suitable vaccination vectors need to be designed that allow the efficient local induction of specific TRM and that do not result in unwanted side effects such as bystander-induced self-reactive TRM. Until now, most research studies have focused on the overwhelmingly positive role of TRM acting against infected or tumorous cells, however we still lack an appropriate understanding of the possible physiological consequences of TRM persistence. Further research efforts are warranted to better understand the role of TRM in chronic inflammatory diseases in order to identify the risks in amplifying TRM numbers or function. So far, we are lacking appropriate mouse models allowing specific genetic targeting of TRM and are not able to completely deplete already-established TRM. It is therefore instrumental to perform detailed preclinical and clinical studies to gain more insight into TRM biology and its adaptation during different experimental regimens and in different tissues to allow for a safe and efficient therapeutic tissue targeting of TRM.
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.