key: cord-0856520-8ed8qf0d
authors: Choi, Hanbyeul; Song, Heonju; Jung, Yong Woo
title: The Roles of CCR7 for the Homing of Memory CD8+ T Cells into Their Survival Niches
date: 2020-05-20
journal: Immune Netw
DOI: 10.4110/in.2020.20.e20
sha: 9d6ebfd4cae03d2d42deddfca140cbe932db49bb
doc_id: 856520
cord_uid: 8ed8qf0d

Memory CD8+ T cells in the immune system are responsible for the removal of external Ags for a long period of time to protect against re-infection. Naïve to memory CD8+ T cell differentiation and memory CD8+ T cell maintenance require many different factors including local environmental factors. Thus, it has been suggested that the migration of memory CD8+ T cells into specific microenvironments alters their longevity and functions. In this review, we have summarized the subsets of memory CD8+ T cells based on their migratory capacities and described the niche hypothesis for their survival. In addition, the basic roles of CCR7 in conjunction with the migration of memory CD8+ T cells and recent understandings of their survival niches have been introduced. Finally, the applications of altering CCR7 signaling have been discussed.

The defense against pathogens is composed of innate and adaptive immunities. While innate response mounts in a few hours by the recognition of molecular patterns, adaptive immune system takes a few days to initiate Ag-dependent specific response. The adaptive immune system employs B cells, which produce antibodies, and T cells to mediate cellular immunity. One cardinal feature of the adaptive immune system is "memory" response to the same Ag. Once the adaptive immune system has been stimulated with vaccines or pathogens, challenges with the same Ag induce a faster and stronger response than the primary response. These memory responses are mainly mediated by Ab-producing plasma cells and memory T (T M ) cells. Through these memory responses, vaccines can protect our body against fatal or serious infectious agents. Although vaccination is the most efficient way to prevent infectious disease, few vaccines have been developed to induce functional T M cells for certain infectious diseases, which is probably because of the lack of knowledge about T M cell development and homeostasis.

Migratory capacity is another important feature of the adaptive immunity, which enables adaptive immune cells to circulate constantly among tissues. Depending on their activation status, these cells generally circulate throughout the body to search for their cognate Ags. For example, naïve T cells are activated with Ags in the secondary lymphoid organs (SLOs) where adaptive immune responses initiate. When T cells are properly activated, they develop into effector T (T E ) cells and migrate into infected sites. While effector CD4+ T cells provide "help" to other immune cells, effector CD8+ T cells, also called CTLs, kill infected or damaged cells. Hence, T cell homing is crucial to fight against invading pathogens so that their migration is tightly regulated. It has been well documented that stimulation of chemokine receptors and adhesion molecules on T cell surface allows for an orderly access to a specific microenvironment. Therefore, it is known that various chemokine receptors are sequentially expressed in the course of immune response to pathogens. Recently, the migratory capacities of T M cells have been highlighted because their recall response and survival are affected by their localization.

In this review, we discussed memory CD8+ T cells and their migratory capacities, particularly the C-C chemokine receptor 7 (CCR7)-dependent pathway, for their survival and longevity. We also highlighted recent studies describing the expression of CCR7 and its ligands, CCL19 and CCL21.

Naïve CD8+ T cells constantly circulate throughout the body through SLOs including the lymph nodes (LNs), spleen, and Peyer's patches (PPs) (1) (2) (3) (4) . The activation of T cells was first reported in 1970s using a mouse model of lymphocytic choriomeningitis virus (LCMV) infection (5, 6) . During viral infections, antigen presenting cells (APCs) such as dendritic cells (DCs) obtain viruses and migrate into the SLOs where naïve T cells search for their cognate Ags. Activated CD8+ T cells by these APCs undergo several pathways to proliferate and gain effector functions important to fight against infectious agents. In addition, CD8+ T E cells modulate the expression of their homing receptors to egress from the SLOs and move into the infected area to induce protective immunity (7, 8) . After the pathogens are cleared, majority (up to 90%) of the activated CD8+ T cells dies, while only a fraction (up to 10%) survives and are maintained as T M (9) cells. These T M cells survive for an extended period of time and provide rapid and robust secondary response to the same Ag. In addition, they undergo self-renewal without Ag exposure and subsets of T M cells undergo a series of steps to re-circulate the whole body searching for re-infections. These prominent characteristics enable T M cells to fight against secondary infections with the same pathogens efficiently (10).

CD8+ T M cells with these cardinal characteristics can be categorized into diverse subsets including effector memory T (T EM ) (11) , central memory T (T CM ), and tissue-resident memory T (T RM ) cells ( Fig. 1) (12) . These subsets were initially identified based on their differential localizations by the expressions of homing receptors, but they also differ from each other in terms of their cytokine production and proliferation capacities. These abilities are regulated by a series of expression of their receptors, signaling molecules, transcription factors, and other important factors. Of note, different subsets of T M cells form depending on the tropism and characteristics of infectious agents and these subsets cooperate to eradicate infections.

T CM cells monitor infection in the body by circulating in the SLOs. In contrast, T EM and T RM cells do not survey SLOs and are located in peripheral tissues (Fig. 1) . However, T EM cells can return to the SLOs if the Ags exist in the SLOs even after Ag is cleared in the infected target area (13) (14) (15) (16) . In 2009, Gebhardt et al. (17) reported that T RM cells stay in the non-lymphoid tissues (NLTs) without returning to the SLOs. They prepare to fight against local infections and are found in many different organs including the brain, lung, gut, skin, and other peripheral organs (18) (19) (20) .

The generation of specific subsets of CD8+ T M cells has been attempted using different animal models. It is generally assumed that systemic infections or vaccinations can induce T CM and T RM cell formation, while local infections induce T RM cell development (21) . Thus, Ag tropism or location determines the fate of T M cells. In addition, the generation of certain subsets may be crucial to protect against specific pathogens (22) . For example, the presence of T RM cells in the liver substantially enhances protection against Plasmodium (23) . Altogether, the modulation of T M cell mobility would benefit our body to fight properly against pathogens by placing T M cells in proper positions.

A remarkable aspect of T M cells is their longevity and homeostasis without further antigenic stimulation. The underlying mechanisms of their homeostasis are based on the exposure to the homeostatic cytokines such as IL-7 and -15 (24) (25) (26) (27) (28) (29) (30) (31) . IL-7 has been well documented as a survival cytokine of naïve, memory precursor (MP) and T M cells. This cytokine is provided by stromal cells including fibroblastic reticular cells (FRCs) in the spleen and LNs (32) (33) (34) . In conjunction with IL-7, IL-15 can induce homeostatic proliferation of T M cells. IL-15 also helps for the survival of KLRG1 hi terminally differentiated T E and T M cells. Therefore, it is crucial for T M cells to "see" these cytokines in order to develop and maintain homeostasis. These subsets are identified on the basis of differential expressions in several chemokine receptors and adhesion molecules. While T CM cells express high levels of CCR7 and CD62L (L-selectin) (CCR7 hi CD62L hi ), T EM cells express low levels of CCR7 and CD62L (CCR7 lo CD62L lo ). These phenotypes indicate that T CM cells circulate to SLOs, whereas T EM cells circulate to peripheral organs. T RM cells express low levels of CCR7 and high levels of CD69 and CD103 (CCR7 lo CD69 hi CD103 hi ) to remain in peripheral organs.

T M cells develop and maintain in multiple organs including the spleen, LNs, liver, lung, and bone marrow (BM) (35). After systemic infection, T M cells can survive and proliferate in these organs, particularly in the BM (36). However, different T M cell subsets are differentially localized within different organs, suggesting that these cells may be exposed to different survival factors depending on their location (37,38). Since leukocyte recruitment is tightly regulated, it is interesting to understand the homing of each subset.

CCR7 is a lymphocyte-specific G-protein-coupled receptor with 7 transmembrane spanning alpha helices for CCL19 and CCL21 as ligands. It was first named Epstein-Barr virus (EBV)indicted gene 1, a gene induced by EBV and Burkitt's lymphoma cells in B-lymphocytes. In the same study, it was shown that it plays an important role in response to virus infection and is detected only in B-and T-lymphocytes (39,40).

In the late 1990s, a study using CCR7-deficient mice showed that CCR7 plays an important role in controlling T cell movement to SLOs, particularly LNs and PPs. In addition, the formation of T cell zone was abolished due to abnormal T cell migration. After immunization, the migration of mature skin DCs into the LNs resulted in delayed immune response to injected Ags (41,42). Based on this observation, CCR7 has been established as one of the crucial receivers responsible for lymphocyte homing (41).

Among the CD8+ T cells, naïve and T CM cells generally express high levels of CCR7 (3,12,43,44), hence they can migrate to the T cell zone of the LNs and spleen. These T cells can be activated in the T cell zone by the APCs and developed into T E cells. During this process, T E cells can move from the T cell zone to the red pulp and the infected area by the downregulation of CCR7 expression (45). Through this regulation of CCR7 expression, CD8+ T cells can find their cognate Ag in the SLOs to be activated and migrated into infected locus. After infections are cleared, T M cells form and circulate to different parts of the body based on the levels of CCR7 expression (45-47).

During T E -T M cell transition, CCR7 expression influences the fate of these cells. It was reported that the mRNA levels of CCR7 were more pronounced in memory precursor T cells (MPECs) than in short-lived effector cells (SLECs) (48). In addition, the T CM and T EM cells were found in different locations of the SLOs depending on CCR7 concentration.

CCR7 expression was inhibited in T RM cells, the recently identified T M cell subset, making it possible for T RM cells to act as the first line of defense within peripheral tissues (49). Altogether, the regulation of CCR7 expression controls the recruitment and release of CD8+ T cells from SLOs, determining the CD8+ T cell response outcome.

The expression of CCR7 on CD8+ T cells is regulated by several transcription factors. In the CCR7 promoter region, there are 3 binding sites specific for protein 1 (Sp1) and one Ets-1binding site (50), which suggests that the increased expression of CCR7 is mediated at least 4/15 https://doi.org/10.4110/in.2020.20.e20 CCR7 Influences the Fate of Memory CD8+ T Cells https://immunenetwork.org partially by transcription factors such as Sp1 and Ets-1 (Fig. 2) (35,50). AP1 and NF-κB were also reported to upregulate CCR7 expression via binding to the CCR7 promoter locus in various cancer cell lines (51-53). In addition, Krüppel-like factor 2 (KLF2) and T cell factor 1 (TCF1) are significantly upregulated in naïve and T CM cells and regulate the expression of several molecules including CCR7, CD62L (L-selectin; encoded by Sell), and sphingosine-1-phosphate receptor 1 in order to modulate the migration into the SLOs (54) . In contrast, CD8+ T EM and T RM cells suppress KLF2 and TCF1, while simultaneously expressing Blimp-1 and suppressing the transcription of CCR7 independently (55) (56) (57) .

It was also reported that Forkhead O 1 (FOXO1), another transcription factor, regulates CCR7 transcription during T E -T M cell transition, and not during naïve-CD8+ T E cell transition. A study using FOXO1 knockout (KO) mice demonstrated that FOXO1 promoted enrichment of MP cells, thus wild-type T E cells highly proliferated upon secondary infections in CD8+ T cells compared to FOXO1-deficient T E cells (58) . In a related study, it was observed that FOXO1 expression is significantly higher in MPECs than in SLECs, and it increase the levels of IL-7Ra and TCF7 expression to help create and maintain T CM cells which were derived from MPECs (59).

CCR7 expression is also controlled by miRNAs. MiRNAs consisting of small RNA fragments under 23 nucleotides generally bind to 3' UTRs of complementary target sequences on target mRNAs to decay or stabilize the mRNA (60). Using big data analysis, several T-cell-associated genes including CCR7 were discovered to be targeted by miR-21, an anti-apoptotic factor (61-63). MiR-21, a miRNA inhibiting post-transcription levels of CCR7, led to a significant reduction of CCR7 protein expression when naïve and CD4+ T M cells are activated. Indeed, it is activated in inverse correlation to the amount of CCR7 protein (Fig. 2) (64) . Further, it was reported that the expression of CCR7 was adjusted by miRNAs in several cancers, such as let-7α (in breast cancer cells and patients) (65), miR-320d (in oral squamous cell carcinoma) (66), miR-532-3p (in tongue squamous cell carcinoma) (67) and head and neck squamous cell carcinoma (68) , and miR-199a (in human mantle cell lymphoma) (69).

Although there is little report of epigenetic regulators for CCR7, it has been documented based on CCR7 gene methylation using big data analysis. CCR7 methylation in human CD8+ T M cells increased in the order of CD8+ T M cell differentiation state: naïve<T SCM (stem cell memory)<T CM <T EM , when this locus was analyzed using whole-genome bisulfite sequencing, a next-generation sequencing method (Fig. 2) (4) . As the DNA methylation state is known as silent chromatin (called as heterochromatin), the expression of the gene was inhibited (70) . Another report showed that monocyte-derived DCs in the mouse lung homing into SLOs are significantly lower in number than conventional DCs. In correlation with this observation, monocyte-derived DCs was highly methylated in H3K27 (H3K27me3), which forms heterochromatin, thus blocking their homing into the SLOs (71).

CCR7 can also be regulated by PTM (Fig. 2) . Glycosylation in the N-terminus of CCR7 protein in T E cells not only blocks, but also decreases receptor sensitivity, resulting in chemokineinduced downstream signaling modulation. It was also reported that de-glycosylation with enzymes produced by DCs changed the folding of CCR7 protein to increase the activity of this receptor (9) . Conversely, the induction of sulfation in tyrosine residue of the CCR7 protein N-terminus can increase the affinity between CCR7 and its ligands (72) .

Altogether the expression of CCR7 can be altered by many different factors in several steps, possibly indicating that the regulation of this receptor is critical for the immune response to pathogen. In addition, it has been suggested that this receptor can be modulated using multiple methods in order to enhance adaptive immunity.

CCR7 hi CD8+ naïve and T M cells have chemotaxis features toward CCL19 and CCL21 in a concentration-dependent manner (73) (74) (75) (76) . These chemokines were reported to be produced by high endothelial venules (63) in the T cell zone of SLOs (77, 78) . When naïve T cells enter the SLOs, they are located in the T and B cell zones. Particularly, naïve CD8+ T cells with CCR7 expression are enriched by FRCs in the T cell zones within the spleen and LNs, where CCL19 and CCL21 are highly enriched (33,79). Correlated with the role of these chemokines, the rate of movement of naïve T cells in the SLOs decreases in plt/plt mouse (paucity of LN; naturally weak CCL19 and CCL21 mutant mice) regardless of T cells lacking CCR7 (80, 81) .

In the CCL21-deficient-special niche, CCR7-positive naïve and T M cells circulate themselves within the interstitial lymphoid organs after being ejected from SLOs.

The quality and quantity of these microenvironmental niches were dynamically changed by several factors during the state of immune responses. Among these factors, IFN-γ, an antiviral-related cytokine, can transiently but substantially downregulate the expressions of CCL19 and CCL21 in the spleen and LNs. During viral infections, IFN-γ is released by effector immune cells including CD8+ T E cells, which then reduces the concentration of CCL19 and 6/15 https://doi.org/10.4110/in.2020.20.e20 CCR7 Influences the Fate of Memory CD8+ T Cells https://immunenetwork.org CCL21 in the T cell zone of the SLOs. In turn, T E cells escape SLOs possibly due to the low levels of CCL19 and CCL21 (82) . CCL21 was also reported to participate in cancer metastasis. Certain types of cancer cells express CCR7, so that they have the ability to migrate towards the SLOs, particularly LNs (83) . This migration facilitates cancer metastasis by pushing cancer cells into lymphatic vessels through LNs. Indeed, the patients with CCR7-positive tumors have significantly poorer prognosis than the patients with CCR7-negative tumors (84) (85) (86) . These studies showed that the regulation of these chemokines is also important for the movement and localization of T and cancer cells.

Survival cytokines are required for the longevity of T M cells; however, it is incompletely defined how these cells "see" these cytokines. There are at least 2 possible explanations for these mechanisms. One hypothesis is systemic exposure, where one organ provides these cytokines and T M cells recognize them anywhere in the body. Another possibility is that these cytokines are present only in specialized microenvironments called niches and T M cells need to home these anatomical locations to receive the required signals. Although systemic exposure cannot be ruled out, evidence have been accumulated to explain the niche hypothesis. First, BM is the preferred site for the homeostatic proliferation, suggesting that survival cytokines are provided locally. Second, differential localization of T E cell subsets within the organ may indicate that they receive different signals depending on their location (37,38). Third, IL-7 has been suggested to be bound to the extracellular matrix near the IL-7 producers (87). Finally, IL-15 has been shown to be trans-presented so that cell-to-cell contacts with IL-15 presenting cells are required for optimal simulation (88) . Altogether, it is strongly suggested that T M cells migrate to specialized microenvironments within the organ in order to survive.

Among the cytokines that are critical for T M cells, it is known that CCL19 and CCL21 maintain a collaborative relationship with IL-7 and IL-15 (Fig. 3) (89) . A rich CCL19 within the LNs works in conjunction with IL-7 to improve the survival of the T cells, but no exact mechanism has been identified (33). Whereas, the adjustment of CD8+ T M cells by IL-15 was found within the NLTs, such as the BM and lung, where distinct from SLOs with large amount of CCL19 and CCL21 (36,90). This implies that the importance of the physical microenvironment is formed by CCL19 and CCL21, as well as sufficient CCR7 expression within the T cells.

To understand the roles of CCR7, Junt et al. (91) first reported normal T cell response to viral infection in plt/plt mice with spontaneous mutations in CCL19 and CCL21 locus. Thus, the viral clearance and secondary response to the same pathogen were comparable to those in littermate controls. However, they also observed that the formation of T M cells were significantly reduced, when CCR7-deficient mice were infected with the same virus (92) . It was also observed that viral clearance in CCR7 KO mice was slower than that in wild-type mice, if completely cleared. Probably due to the reduced number of T M cells, CCR7-deficient mice contained reduced number of IFN-γ + CD8+ T cells in response to secondary infections. Since 2 different results were reported, it was suggested that plt/plt mice express CCL21b, 7/15 https://doi.org/10.4110/in.2020.20.e20 CCR7 Influences the Fate of Memory CD8+ T Cells https://immunenetwork.org a leucine isoform of CCL21, in lymphatic vessels. In addition, CCL21b was also found in peripheral tissue; thus, the recruitment of CCR7 hi cells into the peripheral tissues was compensated (78, 93) . In agreement with this report, mice with ubiquitous overexpression of CCL21 showed abnormal viral clearance (94) . These altered immune responses are not restricted to viral infections, because CCR7 KO mice mounted reduced inflammation in response to Toxoplasma gondii infection, an intracellular protozoan parasite (95) .

In order to exclude the possibility of delayed viral clearance and emphasize the role of CCR7 in the fate decision of CD8+ T M cells, P14 transgenic mice, which recognize the D b GP 33-41 epitope of LCMV, were employed (90) . By transferring small number of CCR7 wild-type or KO P14 CD8+ T cells into wild-type C57/Bl6 mice, these mice were able to clear the viral infection regardless of the genotypes of P14 cells. Using this model, increased number of CCR7 KO T M cells was observed with normal recall abilities. Enhanced survival of CCR7 KO T M cells by IL-15 signaling were found in the lung and BM, because the removal of IL-15, but not IL-7, maintained the comparable number of CCR7-deficient and -sufficient T M cells. In addition, these CCR7-deficient T M cells showed increased ratio of homeostatic turnover compared to CCR7-sufficient cells. These results suggest that CCR7 signaling directs the migration toward IL-7-niches, while CCR7 lo T M cells migrate toward IL-15 niches for their survival. In addition, inhibition of CCR7 signaling may increase the number of T M cells in the lung, where it has been suggested to be difficult for T M cells to survive (Fig. 3) .

When CCR7 was overexpressed in all T cells, the numbers of T M cells in the spleen and LNs of CCR7-tg mice were increased compared to that in wild-type mice, while CCR7-tg T M cell number reduced in the liver and lung. These mice showed difficulty in clearance of skin infection, suggesting that CCR7 forces the migration of T M cells into the SLOs. It would be interesting to see if increased survival of CCR7-tg T M cells in the SLOs is IL-7-dependent. Taken together, the CCR7 expression of CD8+ T M cells determines the fates of CCR7 hi and CCR7 lo CD8+ T cells by properly guiding them into survival niches.

The importance of T M cell subsets has been well documented, and the roles of each subset shed light on individual infectious disease in the last decade. However, it is still not evident how each subset receives crucial signals for their longevity. Accumulating data suggest that specialized niches are present for the survival of T M cells and the migration of MEPCs and T M cells into these niches is crucial for their maintenance. CCR7 may determine the niche suitable for their survival, depending on the subtypes or functions of CD8+ T M cells. Therefore, it can be inferred that CCR7 plays a crucial role in the activation of naïve T cells as well as the development and maintenance of CD8+ T M cell subsets according to these studies.

Currently, the therapies using T cells, such as chimeric Ag receptor T cells, have shown remarkably effective progresses into clinical phases (96) (97) (98) . Despite these successes, the cancer types where these therapies can be applied are limited till date. One of the reasons for this limitation is the type of T cells used in these therapies. Most therapies use naïve or in vitro activated T cells, which can quickly be inactivated in tumor microenvironments. Thus, T M cells have been suggested to be utilized for these applications, particularly since they are seldom exhausted even in various types of immune diseases including cancer, allergic disease, autoimmune disease, and inflammatory bowel disease.

In addition to this suggestion, controlling the migration of T M cells by CCR7 modulation may determine the destiny of CD8+ T M cells by changing their location as discussed in this review. Depending on the diseases or cancers, the localization of T M cells is crucial to promote optimal immune response. Taken together, T M cells may be present and respond effectively at the target sites regardless of whether these sites are present in the SLOs or peripheral organs by inducing or inhibiting the CCR7 signaling in T M cells.

In the past few decades, new respiratory diseases have been caused by virus infections such as influenza virus, severe acute respiratory syndrome coronavirus (SARS-CoV), middle east respiratory syndrome coronavirus, and severe acute respiratory syndrome coronavirus 2 repeatedly. All of these pathogenic viruses were derived from coronaviruses that commonly infect humans, but new mutations have made it difficult for our immune system to get rid of these viral infections. However, the survival of memory CD8+ T cell responding to SARS-CoV in peripheral blood of the patients possibly suggest the importance of T M cells for the recovery from these diseases (99, 100) . Particularly, the Ab response to SARS-CoV was short-lived, indicating the biased immune responses toward T cell immunity. However, it is still not clear whether virus-specific T M cells are also present in the lungs of these survived patients. Since the lungs were proposed to provide unfavorable microenvironments for T M cell homeostasis, it would be particularly challenging to develop proper vaccines or therapies. However, Jung et al. (90) showed that CCR7-deficient T M cells can heavily populate the lung, possibly indicating that the regulation of CCR7 signaling may give us a chance to prevent these diseases. These approaches may illuminate the future of our novel vaccines or therapies. 

Migratory properties of naive, effector, and memory CD8 + T cells

Lymphocyte trafficking and regional immunity

CCR7 expression and memory T cell diversity in humans

Human memory CD8 T cell effector potential is epigenetically preserved during in vivo homeostasis

Twp populations of T lymphocytes immune to the lymphocytic choriomeningitis virus

Functional heterogeneity of lymphocytic choriomeningitis virus-specific T lymphocytes. I. Identification of effector and memory subsets

Selective expression of IL-7 receptor on memory T cells identifies early CD40L-dependent generation of distinct CD8 + memory T cell subsets

Inflammation directs memory precursor and short-lived effector CD8 + T cell fates via the graded expression of T-bet transcription factor

Programming, demarcating, and manipulating CD8 + T-cell memory

High-resolution profiling of histone methylations in the human genome

Switch in chemokine receptor expression upon TCR stimulation reveals novel homing potential for recently activated T cells

Chemokine receptor CCR7 required for T lymphocyte exit from peripheral tissues

Chemokine receptor CCR7 guides T cell exit from peripheral tissues and entry into afferent lymphatics

Tissue-specific migration pathways by phenotypically distinct subpopulations of memory T cells

Activation and migration of CD8 T cells in the intestinal mucosa

Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus

Memory T cells persisting within the brain after local infection show functional adaptations to their tissue of residence

Tissue-resident T cells: dynamic players in skin immunity

A vaccine strategy that protects against genital herpes by establishing local memory T cells

Integrating resident memory into T cell differentiation models

Liver-resident memory CD8 + T cells form a front-line defense against malaria liver-stage infection

Human IL-7: a novel T cell growth factor

Interleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo

Potent and selective stimulation of memory-phenotype CD8 + T cells in vivo by IL-15

Activation of naive and memory T cells by interleukin-15

Effects of interleukin-15 on in vitro human T cell proliferation and activation

Control of homeostasis of CD8 + memory T cells by opposing cytokines

Overexpression of interleukin (IL)-7 leads to IL-15-independent generation of memory phenotype CD8 + T cells

Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8 + cells but are not required for memory phenotype CD4 + cells

Identification of IL-7-producing cells in primary and secondary lymphoid organs using IL-7-GFP knock-in mice

Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells

Decreased expression of sphingosine-1-phosphate receptor 1 in the blood leukocyte of rheumatoid arthritis patients

Blimp-1 transcription factor is required for the differentiation of effector CD8 + T cells and memory responses

Transcriptional repressor Blimp-1 promotes CD8 + T cell terminal differentiation and represses the acquisition of central memory T cell properties

Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes

The transcription factor FOXO1 controls central-memory CD8 + T cell responses to infection

Differentiation of CD8 memory T cells depends on FOXO1

MicroRNAs: target recognition and regulatory functions

miRBase: tools for microRNA genomics

OHM): an online tool to estimate and display hybridizations of oligonucleotides onto DNA sequences

MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells

Dual role of miR-21 in CD4+ T-cells: activation-induced miR-21 supports survival of memory T-cells and regulates CCR7 expression in naive T-cells

MicroRNA let-7a suppresses breast cancer cell migration and invasion through downregulation of C-C chemokine receptor type 7

Interaction between MALAT-1, CCR7 and correlated genes in oral squamous cell carcinoma

MicroRNA-532-3p suppresses malignant behaviors of tongue squamous cell carcinoma via regulating CCR7

Activation of miR-21-regulated pathways in immune aging selects against signatures characteristic of memory T cells

MiR-199a mediated the dissemination of human mantle cell lymphoma by interacting with the CCR7/CCL21 pair

DNA methylation patterns and epigenetic memory

Epigenetic control of Ccr7 expression in distinct lineages of lung dendritic cells

Distinct CCR7 glycosylation pattern shapes receptor signaling and endocytosis to modulate chemotactic responses

CCR7 sulfotyrosine enhances CCL21 binding

Differential regulation of CCL21 in lymphoid/nonlymphoid tissues for effectively attracting T cells to peripheral tissues

CK β-11/macrophage inflammatory protein-3 β/EBI1-ligand chemokine is an efficacious chemoattractant for T and B cells

Epstein-Barr virus-induced molecule 1 ligand chemokine is expressed by dendritic cells in lymphoid tissues and strongly attracts naive T cells and activated B cells

Secondary lymphoid-tissue chemokine is a functional ligand for the CC chemokine receptor CCR7

A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes

Coexpression of the chemokines ELC and SLC by T zone stromal cells and deletion of the ELC gene in the plt/plt mouse

Transcriptional profiling of stroma from inflamed and resting lymph nodes defines immunological hallmarks

CC chemokine receptor 7 contributes to Gi-dependent T cell motility in the lymph node

CCR7 ligands stimulate the intranodal motility of T lymphocytes in vivo

Regulation of homeostatic chemokine expression and cell trafficking during immune responses

Chemokine-mediated migration of melanoma cells towards lymphatics--a mechanism contributing to metastasis

Expression of chemokine receptor CCR7 is associated with lymph node metastasis of gastric carcinoma

Involvement of chemokine receptors in breast cancer metastasis

CCR7 mediates human breast cancer cell invasion, migration by inducing epithelial-mesenchymal transition and suppressing apoptosis through AKT pathway

Mediators of the homeostasis and effector functions of memory Th2 cells as novel drug targets in intractable chronic allergic diseases

Coordinate expression and trans presentation of interleukin (IL)-15Rα and IL-15 supports natural killer cell and memory CD8+ T cell homeostasis

Cytokine control of memory T-cell development and survival

CCR7 expression alters memory CD8 T-cell homeostasis by regulating occupancy in IL-7-and IL-15-dependent niches

Antiviral immune responses in the absence of organized lymphoid T cell zones in plt/plt mice

Impact of CCR7 on priming and distribution of antiviral effector and memory CTL

Ectopic expression of the murine chemokines CCL21a and CCL21b induces the formation of lymph node-like structures in pancreas, but not skin, of transgenic mice

Abrogation of CCL21 chemokine function by transgenic over-expression impairs T cell immunity to local infections

CCR7-dependent immunity during acute Toxoplasma gondii infection

Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia

Chimeric antigen receptor T cells for sustained remissions in leukemia

Biomarkers in chimeric antigen receptor T-cell therapy

Virus-specific memory CD8 T cells provide substantial protection from lethal severe acute respiratory syndrome coronavirus infection

Memory T cell responses targeting the SARS coronavirus persist up to 11 years post-infection

We thank Sang-Hoon Kim and Aryeong Choi for their useful and constructive suggestions on this review. This work was supported by the National Research Foundation of Korea (NRF) funded by Ministry of Education, Science and Technology (NRF-2019R1A6A1A03031807).