ReviewHuman Immunology

Resident memory T cells in human health and disease

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Science Translational Medicine  07 Jan 2015:
Vol. 7, Issue 269, pp. 269rv1
DOI: 10.1126/scitranslmed.3010641


Resident memory T cells are non-recirculating memory T cells that persist long-term in epithelial barrier tissues, including the gastrointestinal tract, lung, skin, and reproductive tract. Resident memory T cells persist in the absence of antigens, have impressive effector functions, and provide rapid on-site immune protection against known pathogens in peripheral tissues. A fundamentally distinct gene expression program differentiates resident memory T cells from circulating T cells. Although these cells likely evolved to provide rapid immune protection against pathogens, autoreactive, aberrantly activated, and malignant resident memory cells contribute to numerous human inflammatory diseases including mycosis fungoides and psoriasis. This review will discuss both the science and medicine of resident memory T cells, exploring how these cells contribute to healthy immune function and discussing what is known about how these cells contribute to human inflammatory and autoimmune diseases.


Resident memory T cells (TRM) are a recently described subset of memory T cells that persist long-term in peripheral tissues. TRM undergo a distinct differentiation program that discriminates them from circulating T cells; this program likely evolved to populate epithelial barrier tissues—skin, gut, lung, and reproductive tracts—with highly protective T cells specific for the pathogens most commonly encountered through each tissue (1, 2). In this way, the immune system distributes memory T cells to the tissue sites where they will likely to be needed in the future. However, dysregulation of TRM can contribute to human autoimmune and inflammatory diseases. TRM differentiate and accumulate in tissues after pathogen infection, but evidence suggests that they also develop after sensitization to otherwise harmless environmental or self antigens. Pathogenic autoreactive TRM induce the fixed, recurrent skin lesions of psoriasis, and TRM specific for environmental allergens likely underlie the development and worsening of allergic asthma and contact dermatitis. Moreover, the TRM differentiation program is likely also engaged when T cells are activated in nonbarrier tissues such as the kidney, brain, and joints. As a result, pathogenic TRM likely contribute to chronic inflammatory diseases in nonbarrier tissues as well. This review will discuss both the basic biology and human diseases associated with TRM, exploring how these cells support healthy immune function and contribute to human inflammatory disease.


In the last decades, it was thought that tissue-tropic T cells remained in the circulation until recruited to sites of inflammation and that noninflamed peripheral tissues contained very few T cells. T cells recruited to tissues during infections were thought to either exit tissues or undergo apoptosis after clearance of the infection. However, CD8+ T cells that remained long-term in mouse lung after influenza virus infection were observed as early as 2001 (3, 4), and antigen-specific CD8+ T cells were found to migrate to nonlymphoid tissues and remain as long-lived memory cells after infections with Listeria and vesicular stomatitis virus (5). In 2004, it was observed that skin grafts of normal-appearing, nonlesional skin from psoriatic patients gave rise to active psoriatic skin lesions after transplantation onto immunodeficient mice, demonstrating that a population of resident pathogenic T cells existed in the nonlesional skin of patients with psoriasis (6, 7). Subsequently, it was discovered that the healthy skin surface of an adult human being contained nearly 20 billion T cells, about twice as many as are present in the entire blood volume (8). Human skin T cells were all CD45RO+ memory T cells, coexpressed the skin-homing addressins CLA and CCR4, and had potent effector functions and a diverse T cell repertoire (811). Studies designed to determine the location of skin-tropic memory T cells found that 98% were located in human skin under noninflamed conditions, and only 2% were in the circulation (8). These findings challenged the idea that T cells must be recruited from peripheral blood during infectious challenges and suggested that at least some subsets of tissue-tropic T cells spend most of their time in peripheral tissues. Subsequent studies demonstrated large numbers of antigenically diverse TRM in human lung, gastrointestinal tract, peritoneum, reproductive tract, and bone marrow (1219).


The large number of memory T cells in human epithelial barrier tissues is consistent with the idea that some T cells may reside long-term in peripheral tissues, but a series of elegant mouse models were required to clarify how these cells are generated, distributed, and maintained. Mice kept in clean, pathogen-free barrier facilities had few skin TRM, likely because these cells are generated by the infections barrier facilities are designed to prevent. However, experimentally administered skin infections with herpes simplex virus (HSV) and vaccinia virus both generated populations of CD8+ T cells that remained in the skin long after resolution of the acute infection and provided rapid viral clearance after skin reinfection (2024). Dendritic cells were capable of presenting antigen to local populations of HSV-specific TRM, leading to a local recall immune response entirely within the skin (25). TRM generated by prior vaccinia skin infection were more protective than circulating T cells and rapidly cleared virus from the skin after reinfection in the complete absence of both antibodies and circulating T cells (21, 23, 24). Moreover, local skin infection with vaccinia virus led to seeding of the entire cutaneous surface with long-lived, highly protective TRM, although the highest concentration of these cells occurred at the site of infection (21) (Fig. 1). Subsequent reinfections at different skin locations led to progressive increases in the number of protective TRM throughout the skin; in this way, local skin infections led to a global protection of the entire skin by long-lived, highly protective TRM (21). Preferential deposition of TRM at inflammatory sites after HSV infection was found to be antigen-independent (22). TRM progenitor cells generated by recent skin infection migrated in greatest numbers into areas of inflamed skin, regardless of whether the inflammation was caused by local HSV infection or by irritation of the skin by the contact allergen 2,4-dinitrofluorobenzene (22).

Fig. 1. Local skin infection leads to seeding of the entire skin surface with protective TRM.

After a localized skin infection with vaccinia virus in mice, highly protective virus-specific TRM were generated (1) that remained long-term in the skin and provided local protection against reinfection (21). TRM were most numerous at the site of initial infection (2), but these cells were also found in lower numbers in never infected skin (3).

The best possible outcome of vaccination is the generation of highly protective TRM in the epithelial barrier tissue most likely to be re-infected. Skin scarification with live vaccinia virus, associated with local keratinocyte infection, generated long-lived CD8+ T cell–mediated immunity that was 100,000 times more effective than subcutaneous, intradermal, and intramuscular vaccination in protecting against viral reinfection of the skin (24). This protection was mediated entirely by skin TRM and did not require antibodies or recruitment of circulating T cells from blood (21, 24). These studies call into question the current vaccination strategy of injecting vaccines into muscle. Muscle lacks a resident population of antigen-presenting cells, and intramuscular vaccination is unlikely to effectively focus immune responses to the relevant peripheral tissues.

A surprising additional benefit of local skin infection with vaccinia was the generation of a smaller but functionally important population of lung TRM that could, in the absence of antibody and circulating T cells, partially protect mice from an otherwise lethal pulmonary challenge with vaccinia virus (23, 24). This spillover of immune protection occurred as a result of early release from skin draining lymph nodes of a subset of T cells proliferating in response to antigen after skin infection. These released T cells traveled to distant lymph nodes draining other peripheral tissues where they continued to proliferate in the absence of antigen and developed tissue tropism for these distinct, noncutaneous tissues (23) (Fig. 2, right panel). In other words, local infection of one barrier tissue led to at least some immune TRM-mediated protection of other epithelial barrier tissues. A similar mechanism clearly exists in humans, where smallpox vaccination, delivered by skin scarification, has historically provided effective protection against smallpox, which is primarily transmitted as a respiratory infection (Fig. 2, left panel).

Fig. 2. Local skin infection leads to protective TRM in other epithelial barrier tissues.

After local skin infection with vaccinia virus in mice (1), protective TRM developed not only in the skin but also in lower numbers in the lungs and gastrointestinal tract (2) (23, 24). Lung-resident TRM induced by skin infection provided partial protection against an otherwise lethal pulmonary challenge with vaccinia (3). This protection was found to be mediated by early release of virus-specific T cells proliferating in the skin draining lymph nodes after primary cutaneous infection. These T cells migrated to lymph nodes draining other tissues, proliferated in the absence of antigen, and were imprinted with tropism for these distant tissues (23). Historical evidence suggests that a similar biology exists in human beings. Smallpox vaccination, carried out by skin scarification with vaccinia virus, leads to protection against smallpox, an infection that is acquired via the respiratory route.

The immune protection provided by TRM is more than skin deep; infection models in mouse gut, lung, and reproductive tract confirm that TRM persist, protect, and do not recirculate. Gut infection with lymphocytic choriomeningitis virus, Listeria, and other pathogens generated long-lived intraepithelial T cells with potent protective capacity (26). CD4+ TRM in the lung generated by influenza infection persisted, did not recirculate (14), and provided potent in situ protection against an otherwise lethal influenza challenge (27). Both intranasal and intraperitoneal infections with influenza induced virus-specific effector memory T cells, but only nasal infection generated T cells that mediated protection against an otherwise lethal intranasal influenza challenge (28). In the genitourinary tract, intravaginal infection with HSV induced the accumulation of highly protective TRM (29). Moreover, topical intravaginal chemokine application “pulled” circulating effector T cells generated by subcutaneous HSV infection into the vaginal mucosa where they differentiated into protective TRM. Likewise, intravaginal inflammation induced by topical nonoxynol-9 application pulled circulating HSV-specific effector cells into the vaginal mucosa where they differentiated into protective TRM (22).


Studies in both mice and humans have demonstrated that TRM from peripheral tissues express CD69, and a subset also express CD103 (8, 16, 20, 21, 27, 3032). In mice, epithelium-resident CD8+CD103+ T have been most fully characterized, although CD4+ TRM have also been observed and are in fact the dominant population of TRM in human skin (33, 34). After HSV infection in mice, sessile CD8+ TRM took up residence in the epidermis, whereas CD4+ TRM remained in the dermis and were locally more mobile (33). CD8+ TRM that took up residence in the epidermis after HSV infection in mice progressively displaced existing populations of dendritic epithelial T cells (DETCs) from their epidermal niches (35). In contrast to CD8+ TRM, which take up residence in epidermis only after skin infection, γδ DETCs are present in mouse epidermis before infections, although they are not observed in humans. γδ DETCs were fixed in place within the epidermis, whereas CD8+ TRM moved laterally between keratinocytes, frequently interacting with Langerhans cells, but remained within a limited territory of migration (35). Last, decreased expression of the KLF2 transcription factor leading to sphingosine-1-phosphate receptor 1 (S1P1) down-regulation was also necessary for retention of CD8+ TRM in the skin (36). CD69 suppresses the activity of S1P1, suggesting that CD69 expression by TRM may assist in retaining these cells in peripheral tissues (37).

Gene profiling of CD103+CD8+ TRM isolated from mouse skin, lung, gut, and brain has demonstrated that TRM are the product of a distinct differentiation pathway that renders TRM extracted from different peripheral tissues more similar to each other than they are to circulating T cells (1, 2). The TRM differentiation program is engaged only after migration of recently activated T cells into peripheral tissues such as the skin (1) (Fig. 3). The exact precursor cell type for TRM remains unidentified, but in mice, they are derived from the KLRG1 T cell population (1). Localization of HSV-specific CD8+ TRM in the epidermis was dependent on a chemokine-mediated process that could be inhibited by pertussis toxin. Maintenance of epidermal TRM required interleukin-15 (IL-15), and CD103 expression on these cells was induced in a transforming growth factor–β (TGF-β)–dependent manner after entry into the epidermis (1). A second study confirmed that TGF-β was important for establishing epithelial TRM residence and demonstrated additional requirements for IL-33 and tumor necrosis factor–α (TNFα) (36).

Fig. 3. TRM are generated via a distinct, tissue-induced differentiation program.

Under conditions of both health and disease, antigens are transferred from the skin to the draining lymph nodes, where responding T cells are generated. A subset of these T cells home back to the skin and undergo a distinct TRM differentiation program that is induced only after entry into the peripheral tissues (1, 2). In the case of infectious pathogens, TRM provide rapid local immune protection against reinfection. However, the TRM program can also be engaged after exposure to allergens and autoantigens, and in these situations, pathogenic TRM can be generated in peripheral tissues. In the skin, pathogenic TRM have been demonstrated in psoriasis and fixed drug eruption (5961).

Peripheral tissues also contain populations of recirculating T cells, and one common feature of these T cells is their expression of CCR7. CCR7 expression is required for the exit of T cells from peripheral tissues via the afferent lymphatics (3840). Studies in Kaede mice demonstrated that the skin contained both non-recirculating CD4+CCR7 TRM and recirculating CD4+CD69CCR7+L-selectinlo T cells that exited the skin in a CCR7-dependent mechanism (39). Human skin contains a recirculating population of L-selectin+/CCR7+ central memory T cells (TCM) that coexpress the skin addressins CLA and CCR4 (34).


Mouse model systems have provided invaluable insights into many biologic processes. However, there are significant differences in the immune systems of humans and mice, and these differences remain incompletely characterized. Some mouse models, such as the C3H model for alopecia areata, closely resemble the human disease, but others, including proposed mouse models of psoriasis, only partially recapitulate the human disease (4143). It is therefore critical that observations made in mouse models be confirmed in humans.

Evidence has accumulated that the three critical characteristics of mouse TRM—that these cells persist, protect, and do not recirculate—also hold true in humans. The presence of 20 billion T cells in human skin and the observation that T cell numbers in the skin remain constant even in patients in their 90s is circumstantial evidence that these cells persist long-term (8, 44). However, the persistence and protective nature of human TRM has now has been elegantly and directly demonstrated in studies of patients with genital HSV (45, 46). HSV-specific CD8αα T cells were found to persist at the dermo-epidermal junction long-term after resolution of acute HSV outbreaks (46). During subsequent episodes of subclinical viral reactivation, asymptomatic viral shedding was noted accompanied by HSV protein production by infected keratinocytes. TRM were observed to cluster around the infected keratinocytes and produce perforin. Suppression of viral reactivation was observed when TRM were present in high density, whereas low numbers of HSV-specific TRM were associated with full viral reactivation and progression to clinically apparent lesions (46). These elegant studies, using multicolor immunofluorescence and high-throughput TCR (T cell receptor) sequencing, are illustrative of the elegant work that can now be done to characterize TRM in human tissues.

Additional evidence that TRM in the skin persist, protect, and do not recirculate comes from studies of patients with leukemic cutaneous T cell lymphoma (L-CTCL). Alemtuzumab, an anti-CD52 antibody, used in the treatment of chronic lymphocytic leukemia and CTCL, depletes via antibody-dependent cellular cytotoxicity requiring accessory cells that are most frequent in the circulation (34). Low-dose alemtuzumab treatment depleted all circulating T cells and purged the skin of both malignant and benign L-selectin+/CCR7+ TCM, a skin-tropic subpopulation of highly migratory T cells (34, 47). Despite complete depletion of all circulating and recirculating T cells, low-dose alemtuzumab was not associated in this patient population with an increased risk of infection. Biopsy of the skin demonstrated that large numbers of TRM with marked effector functions and diverse antigen specificities remained in the skin of treated patients. These studies demonstrated that human skin is colonized by a diverse, highly protective, and non-recirculating population of TRM. In addition, these studies demonstrated that a subset of L-selectin+/CCR7+ TCM, a subset of T cells thought to primarily recirculate between the blood and lymph nodes, also express skin-homing addressins in humans and can enter and recirculate through the skin (34).

Large numbers of diverse CD69+ TRM with marked effector functions and enriched for influenza specificity have also been detected in histologically noninflamed human lung (14, 19). CD8+ T cells in human lung expressing the TRM marker CD103 were found to be the subset that were specific for influenza, compared to nonresident T cell populations from the same patients (14, 48). More recent studies in other tissues have demonstrated the presence of TRM in human stomach, colon, small intestine, and cervix (12, 16, 18). CD8+ T cells were excluded from high-grade cervical dysplastic lesions (18), but patients vaccinated against oncogenic papilloma virus proteins had robust T cell infiltration of high-grade cervical intraepithelial neoplasias (49).

Findings in both human and mice suggest that the TRM populations in each epithelial barrier tissue may be enriched for the pathogens commonly encountered through those sites. Although the antigen specificity of TRM in human peripheral tissues has been difficult to interrogate directly, a recent study evaluated the antigen specificity of circulating effector T cells tropic for the skin (CLA+), gut (α4β7 integrin+), and other sites (including lung) (50). T cells tropic for the skin were enriched for specificity against skin-associated pathogens and commensals (Staphylococcus epidermidis, Candida albicans, HSV-1), gut-tropic T cells were enriched for specificity against gut-associated pathogens (Salmonella typhi, rotavirus), and remaining T cells (including lung-tropic T cells) were enriched for pathogens encountered through the lung (influenza A and Mycoplasma).


The TRM genetic differentiation program evolved to progressively populate epithelial barrier tissues with non-recirculating memory T cells with potent effector functions that are specific for the pathogens encountered through those sites. Under conditions of health, these cells provide extremely rapid on-site immune protection against known pathogens. However, when T cells specific for allergens or autoantigens enter peripheral tissues and differentiate into TRM or when TRM themselves become malignant, TRM cease to be the solution and instead become part of the problem (Figs. 3 to 5).

Fig. 4. TRM and skin-tropic TCM give rise to distinct inflammatory lesions in the skin.

CTCLs are a heterogeneous collection of lymphomas derived from skin-tropic T cells. (A) In MF, a skin-limited variant of CTCL, malignant T cells have the phenotype of TRM, do not recirculate, and induce well-demarcated stable inflammatory skin lesions that appear to resolve with topical therapies but often recur after treatment is discontinued (34, 55). (B) In contrast, patients with L-CTCL have malignant T cells that coexpress both TCM markers (L-selectin and CCR7) and skin-homing addressins (CLA and CCR4) (55). These T cells recirculate between the blood and skin (34), likely also enter lymph nodes, and give rise to diffuse erythema of the skin. Clinical images are included with patient permission.

Fig. 5. TRM in human autoimmune, inflammatory, and allergic disorders.

Pathologic TRM have been directly demonstrated in psoriasis, MF, and fixed drug eruption (shown in bold), but the clinical characteristics of many other human inflammatory diseases suggest a role for TRM. Clinical characteristics of TRM-mediated diseases include recurrent inflammation in the same anatomic locations, discrete and well-demarcated inflammatory lesions, rapid onset of inflammation within 12 to 24 hours, and progressively worsening disease with subsequent exposures.

The clinical characteristics of TRM-mediated human diseases reflect TRM biology. Because TRM do not recirculate, inflammatory lesions caused by TRM tend to be well demarcated, with distinct margins and an abrupt cutoff with normal tissue (Fig. 4). TRM-mediated lesions tend to persist long-term in a particular location and, although they may appear to resolve with anti-inflammatory therapy, will often recur in the same location and grow to the previously observed size after therapy is discontinued if the inciting agent is still present. Because TRM are already on site and can respond to antigen presented by local tissue-resident dendritic cells (25), TRM-mediated tissue inflammation is extremely rapid and can occur within hours of antigen exposure. In general, onset of inflammation within 24 to 48 hours after antigen exposure is suspicious for TRM involvement. Last, because of the tendency of TRM to progressively accumulate in tissues with repeated antigen exposures, TRM-mediated inflammatory diseases tend to worsen over time, with an increasingly rapid onset of inflammation and increasing inflammatory severity with each exposure.


Mycosis fungoides

CTCLs are a heterogeneous collection of non-Hodgkin’s lymphomas derived from T cells that traffic to the skin. The common feature of all CTCL variants is the formation of inflammatory skin lesions caused by malignant T cells. However, CTCL patients can have different clinical presentations and prognoses. Patients with mycosis fungoides (MF), a relatively benign skin-limited variant of CTCL, have malignant T cells that are found only in well-demarcated fixed inflammatory skin lesions (Fig. 4A). These inflammatory lesions often persist for decades and, although they may appear to resolve with topical steroid therapy, usually recur in the same locations once therapy is discontinued. About 80% of patients with MF will have stable disease and a normal life expectancy (51). Patients who progress often develop tumors and worsening skin disease but rarely develop circulating malignant T cells. In contrast, patients with L-CTCL, including Sézary syndrome, have malignant T cells that accumulate in the skin, blood, lymph nodes, and sometimes other organs. These patients tend to present with patchy, ill-defined inflammatory skin lesions or with diffusely erythematous skin (erythroderma, Fig. 4B). Patients with L-CTCL have an average life expectancy of 3 to 4 years, definitive cure requires stem cell transplantation, and patients die most commonly from infections (52).

MF and L-CTCL were previously thought to represent stages in a disease continuum, but most patients present with either one subtype or the other (51). More recently, profiling and phenotypic studies of malignant T cells have suggested that these variants actually represent lymphomas derived from distinct T cell subsets (5355). Malignant T cells in MF lacked L-selectin and CCR7 expression and phenotypically resembled TRM, consistent with their tendency to form fixed inflammatory skin lesions (55). In contrast, malignant T cells in L-CTCL, whether they were isolated from the blood or inflamed skin, coexpressed L-selectin and CCR7 along with the skin-homing addressins CLA and CCR4 (34, 55). These skin-tropic TCM are observed in healthy human skin as well and would be expected to recirculate between the blood lymph nodes and skin, exactly the tissues involved in patients with L-CTCL (34).

The most effective treatment modalities for these disorders reflect the biology of the T cells that cause them. MF responds, at least temporarily, to skin-directed therapy with topical steroids, retinoids, nitrogen mustard, phototherapy, and low-dose irradiation, whereas L-CTCL patients require systemic therapies and, eventually, stem cell transplantation (52). We found that alemtuzumab, a humanized monoclonal antibody against CD52, depletes circulating and recirculating T cells in L-CTCL but spares TRM in the skin. This medication is effective in L-CTCL and completely ineffective in MF (34).


Psoriasis is a prototypic TRM-mediated autoimmune inflammatory skin disease and a uniquely human problem. Mouse models recapitulate some of the histologic disease features, but mice do not spontaneously develop psoriasis. As a result, most insights into the biology of psoriasis have resulted from observing patient responses to clinical therapeutics. The findings that T cell immunosuppressive medications, such as cyclosporine, suppress psoriatic symptoms pointed to a T cell–mediated etiology for this disease, as opposed to a primary keratinocyte abnormality (56). Most recently, complete responses of patients to the IL-17A inhibitor secukinumab have demonstrated that psoriasis is, at its core, an IL-17–mediated disease (57). One of the chief frustrations of physicians and sufferers of psoriasis is the fact that psoriatic skin lesions occur to completely resolve with therapy but often recur in the same locations, regrowing to their prior size, once therapy is discontinued.

The first clue that psoriasis may be a TRM-mediated disease came from the surprising clinical observation that blockade of E-selectin, which blocks the migration of T cells from the blood into the skin, was completely ineffective in the treatment of psoriasis (58). Next came a groundbreaking set of experiments in which nonlesional, normal-appearing skin grafts derived from patients with psoriasis developed full-blown psoriatic lesions when transferred onto immunodeficient mice (6). These lesions resulted from activation and proliferation of a presumably autoreactive T cell population transferred with the normal-appearing skin graft. These experiments demonstrated that autoreactive pathogenic T cells were present in even the normal healthy-appearing skin of patients with psoriasis and that psoriatic skin lesions can develop in the complete absence of any recruitment of cells from blood. Gene profiling studies of active psoriatic lesions and previously lesional, normal-appearing skin after treatment with TNFα blockade demonstrated persistently abnormal expression of a subset of genes, including CD8 (59). Histologic studies demonstrated that there was a residual resident population of CD8+ T cells in previously lesional psoriatic skin (59). More recent studies demonstrated that CD4+ cells making IL-22 and CD8+ cells making IL-17 remained resident in previously lesional psoriatic skin after clinical resolution with a number of effective psoriatic therapies (60). These studies definitively demonstrate that TRM persist in clinically resolved psoriatic lesions and produce the cytokines known to cause the primary pathology of this disease.


In the skin, histologic studies also support TRM as the cause of fixed drug eruption, a cutaneous eruption consisting of a single or few inflammatory skin lesions that occur after taking a particular medication. Once the medication is discontinued, these lesions appear to completely resolve, only to recur in exactly the same places years or even decades later when the medication is taken again. Histologic stains demonstrated the presence of a resident population of CD8+ T cells producing interferon-γ in sites of resolved fixed drug eruption lesions, supporting a role for TRM in this process (61). Other fixed, rapidly recurrent, and progressively worsening cutaneous eruptions including vitiligo, contact dermatitis, and chronic lesions of eczematous dermatitis are likely to involve TRM, but this has not been directly demonstrated (Fig. 5).

Inflammatory diseases in other barrier tissues, including the gut, lung, and genitourinary tracts, have clinical characteristics that suggest TRM participation. Asthma, other allergic airway diseases, food allergies, and celiac sprue show a rapid onset of inflammation, at least some of it T cell–mediated, after antigen exposure (62). Crohn’s disease produces areas of discrete gut inflammation separated by normal-appearing mucosa, known as “skip lesions,” which are morphologically similar to the well-demarcated skin lesions seen in TRM-mediated skin disease. However, TRM presence, generation, and pathogenicity have yet to be directly demonstrated in these disorders.

Although the TRM genetic differentiation program likely evolved to populate epithelial barrier tissues with protective T cells, T cells responding to inflammation in other tissue sites can also give rise to TRM and corresponding pathology at the sites (Fig. 5). CD103+ TRM with transcriptional profiles distinct from effector T cells and TCM were generated and remained resident within the brains of mice after infection with vesicular stomatitis virus (2). In humans, TRM have been postulated to contribute to brain injury in multiple sclerosis and schizophrenia (63, 64). In mouse models of spondyloarthropathy, entheseal resident TH17 (T helper type 17) TRM were essential for disease progression (65), and recurrence of arthritis in particular joints is a hallmark of human rheumatoid arthritis. Malaria infection led to the generation of TRM in the livers of infected mice (66). In humans, T cells infiltrate the liver in patients with chronic hepatitis C, but these cells have not been definitively identified as TRM (67). In patients with lupus erythematosus and nephritis, individual T cell clones in renal inflammatory infiltrates were found to persist for years in repeat biopsy samples from individual patients, suggesting that TRM may participate in the progressive, devastating kidney damage observed in patients with lupus (68).


In the years to come, it will be critical to determine how long TRM remain in peripheral tissues, how often they turn over, what environmental niches within the peripheral tissue support their continued long-term survival, and what, if anything, can be done to mobilize these cells from peripheral tissues if their presence is detrimental. It will be critical to identify which human diseases have a TRM-mediated component and to evaluate the therapies for their effects on TRM. Many treatment modalities in current clinical use, including total body irradiation, skin brachytherapy, phototherapy, and a variety of systemic chemotherapy drugs, are completely uncharacterized with respect to their effects on TRM. For example, alemtuzumab, a medication previously thought to deplete all T and B cells in the body, depletes only circulating and recirculating T cells but leaves at least skin TRM intact (34). A better understanding of how and where these drugs act on memory T cells could lead to more selective therapies that preferentially target the pathogenic T cells while sparing nonpathogenic T cell subsets.

The discovery and characterization of TRM has proved once again that nature and biology are smarter than we are. A system that distributes memory T cells specific for the pathogens likely to be encountered through those sites directly to the tissues at risk is an elegant way to focus potentially dangerous effector T cells only to the places they are most likely to be needed. Work remains to be done to identify which vaccination strategies generate the greatest number of TRM in the target tissues, and similar approaches are needed to induce the formation of TRM at tumor sites, where they can locally protect against recurrence. However, the strengths of TRM become a problem when these cells are maladaptive and cause inappropriate inflammation. The long-lived, non-recirculating nature of the cells combined with their potent effector functions results in inflammatory diseases that are intransigent and tend to recur in the same anatomic locations. Further studies of the basic biology of these cells may identify an Achilles’ heel in TRM biology that will allow their depletion and local control within tissues.


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