|Coordinate||99,145,277 bp (GRCm38)|
|Base Change||A ⇒ T (forward strand)|
|Gene Name||chemokine (C-C motif) receptor 7|
|Synonym(s)||EBI1, Ebi1h, Cmkbr7, CD197|
|Chromosomal Location||99,144,196-99,155,077 bp (-)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene is a member of the G protein-coupled receptor family. This receptor was identified as a gene induced by the Epstein-Barr virus (EBV), and is thought to be a mediator of EBV effects on B lymphocytes. This receptor is expressed in various lymphoid tissues and activates B and T lymphocytes. It has been shown to control the migration of memory T cells to inflamed tissues, as well as stimulate dendritic cell maturation. The chemokine (C-C motif) ligand 19 (CCL19/ECL) has been reported to be a specific ligand of this receptor. Signals mediated by this receptor regulate T cell homeostasis in lymph nodes, and may also function in the activation and polarization of T cells, and in chronic inflammation pathogenesis. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Sep 2014]
PHENOTYPE: Homozygous mice exhibit an impaired primary immune response. Dendritic cells, B, T and T regulatory cells show impaired migration to the lymph nodes and secondary lymph organs exhibit morphological abnormalities. Lymphocytic infiltrates to the pancreas, lung and stomach are observed in aged mice. [provided by MGI curators]
|Amino Acid Change||Isoleucine changed to Lysine|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000099423]|
AA Change: I273K
|Predicted Effect||possibly damaging
PolyPhen 2 Score 0.899 (Sensitivity: 0.82; Specificity: 0.94)
|Meta Mutation Damage Score||0.6427|
|Is this an essential gene?||Probably nonessential (E-score: 0.217)|
|Candidate Explorer Status||CE: potential candidate; Verification probability: 0.237; ML prob: 0.282; human score: 2|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Last Updated||2019-09-04 9:45 PM by Bruce Beutler|
|Record Created||2015-04-04 7:26 PM by Ming Zeng|
The lanzhou phenotype was identified among G3 mice of the pedigree R1115, some of which showed an increase in the CD4+ to CD8+ T cell ratio in the peripheral blood (Figure 1) caused by an increased frequency of CD4+ T cells (Figure 2).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 35 mutations. The T cell phenotypes were linked by continuous variable mapping to a mutation in Ccr7: a T to A transversion at base pair 99,145,277 (v38) on chromosome 11, or base pair 9,801 in the GenBank genomic region NC_000077 encoding Ccr7. The strongest association was found with a recessive model of linkage to the normalized CD4+ T cell frequency, wherein 4 variant homozygotes departed phenotypically from 19 homozygous reference mice and 11 heterozygous mice with a P value of 7.37 x 10-6 (Figure 3). The mutation corresponds to residue 897 in the mRNA sequence NM_007719 within exon 3 of 3 total exons.
The mutated nucleotide is indicated in red. The mutation results in an isoleucine (L) to lysine (K) substitution at position 273 (I273K) in the chemokine (C-C motif) receptor 7 (CCR7) protein, and is strongly predicted by PolyPhen-2 to cause loss of function (score = 0.899) (1).
|Illustration of Mutations in
Gene & Protein
CCR7 (alternatively, BLR2/EBI-1) is a G-protein-coupled receptor (GPCR) with seven transmembrane domains (amino acids 60-86, 96-116, 131-152, 171-191, 220-247, 264-289, 314-331), three intracellular loops (amino acids 87-95, 153-170, 248-263), three extracellular loops (amino acids 117-130, 192-219, and 290-313), a short acidic N-terminus (amino acids 25-59), and a serine- and threonine-rich C-terminus (amino acids 332-378) (Figure 4) (2). Amino acids 1-24 comprise a signal peptide.
As a GPCR, CCR7 couples with a heterotrimeric G protein to mediate its downstream effects. G proteins, which consist of an α subunit that binds and hydrolyzes GTP (Gα), and β and γ subunits that are constitutively associated in a complex [reviewed in (3); Figure 5]. In the absence of a stimulus, the GDP-bound α subunit and the βγ complex are associated. Upon activation by ligand binding, the GPCR recruits its cognate heterotrimeric G protein, and undergoes a conformational change enabling it to act as guanine nucleotide exchange factor (GEF) for the G protein α subunit. GEFs promote the exchange of GDP for GTP, resulting in dissociation of the GTP-bound α subunit from the activated receptor and the βγ complex. Both the GTP-bound α subunit and the βγ complex mediate signaling by modulating the activities of other proteins, such as adenylyl cyclases, phospholipases, and ion channels. Gα signaling is terminated upon GTP hydrolysis, an activity intrinsic to Gα and one that may be stimulated by GTPase activating proteins (GAPs) such as regulators of G protein signaling (RGS) proteins. The GDP-bound Gα subunit reassociates with the βγ complex and is ready for another activation cycle. Ligand-induced phosphorylation of the GPCR by G protein coupled receptor kinases (GRKs) leads to sequestration of the receptor from the cell surface thereby downregulating signaling. Binding of CCL19/CCL21 to CCR7 activates the G-protein Gαi and the subsequent activation of Jak3 (see the record for mount_tai), PI3 kinase, and phospholipase C β2/β3, which trigger rapid calcium-flux and other downstream signaling molecules such as Src kinases and focal adhesion kinase (FAK), c-Jun N-terminal kinase (JNK), p38 MAPK, ERK and PI3K/Akt [(4-6); Figure 6].
The lanzhou mutation results in an isoleucine (L) to lysine (K) substitution at position 273 (I273K) within the sixth transmembrane domain.
CCR7 is expressed on several immune cell subsets including double negative (DN) thymocytes (7), single positive (SP) thymocytes (7), naïve T cells (8-10), central memory T cells (TCM) (9;11), regulator T cells (Treg) (12), naïve B cells (13), semi-mature and mature dendritic cells (DCs) (14), macrophages (15), and neutrophils (16). CCR7 is also expressed in non-immune cells including various malignancies and astrocytes (17;18). All of the CCR7+ cell types migrate to, and within, lymphoid organs. CCR7+ DN and SP thymocytes migrate within the thymus, CCR7+ DCs migrate from tissues to secondary lymphoid organs (SLOs), and mature CCR7+ T and B cells circulate through SLOs. CCR7 expression on macrophages and neutrophils promotes entry and positioning within SLOs.
A summary of the factors that regulate CCR7 expression is shown in Table 1.
Table 1. Factors that regulate CCR7 expression
Chemokines are chemotactic cytokines that have several functions including regulation of leukocyte trafficking and organization of lymphoid organs. Stromal cells within primary lymphoid organs and SLOs constitutively produce the chemokine ligands of CCR7, CCL19 and CCL21 (28-30). The CCR7/CCL19/CCL21 axis regulates the formation of microenvironments that promote interactions between antigen-presenting cells (APCs) and antigen-specific lymphocytes, an essential process in adaptive immune system function. CCL19 and CCL21 do not mediate overlapping functions. CCL21 is predicted to be a predominantly matrix- and endothelial cell-bound chemokine that promotes chemotaxis and cell adhesion (31). CCL21 can be cleaved to form a soluble form that can promote chemotaxis, but not cell adhesion (31). CCL19 is predicted to be predominantly soluble and stimulates CCR7 phosphorylation and internalization, leading to receptor desensitization [(32;33); reviewed in (34)].
Development of thymocytes into mature T cells occurs in the thymus, where thymocytes follow a program of differentiation characterized by expression of distinct combinations of cell surface proteins including CD4, CD8, CD44 and CD25. The most immature thymocytes are CD4-CD8- double negative (DN). This group can be further subdivided into 4 groups that differentiate in the following order: CD44+CD25- (DN1) to CD44+CD25+ (DN2) to CD44-CD25+ (DN3) to CD44-CD25- (DN4). During this process, expression of pre-TCRα (pTα), TCRα, TCRβ and CD3 proteins is activated in temporal sequence to promote T cell development. The DN3 stage is the first critical checkpoint during thymocyte development. Progression and expansion past DN3 requires surface expression of the product of a productive chromosomally rearranged TCRβ chain, which pairs with an invariant pre-TCRα chain and then forms a complex with CD3 and TCRζ. This complex is known as the pre-TCR and produces a TCR-like signal that is necessary for continued survival. After progressing through the DN4 stage, αβ thymocytes express both CD4 and CD8 and are known as double positive (DP) cells. Progression past this state to single positive CD4 or CD8 cells requires a TCR signal that occurs through a newly rearranged TCRα chain and the previously expressed TCRβ chain.
CCR7 functions at several stages during thymocyte development (Figure 7). CCR7 cooperates with two other chemokine receptors, CCR9 and CXCR4, to promote efficient immigration of circulating bone marrow-derived precursors into the thymus (35-38). CCR7 expression on DN2 cells is required for migration of DN2 cells to the cortex (7). Later in development, CCR7 is required for migration of CD4 and CD8 SP thymocytes back to the medulla where the SP cells undergo negative selection to remove cells that express self-reactive TCRs (39-42). CCR7-deficient thymocytes exhibit impaired TCR signaling necessary for optimal negative selection (40). High concentrations of CCL19/CCL21 initiates an inhibitory program in T cells by interfering with cell proliferation and IL-2 secretion in CCR7+ cells (43). In Ccr7-deficient (Ccr7-/-) mice, CCL19 did not have an inhibitory effect on T cells; Ccr7-/- T cells exhibited TCR-associated proliferation similar to CCL19-treated wild-type cells (43). Proliferation inhibition was associated with influence on cell cycle progression by delayed degradation of the cyclin-dependent kinase (CDK) inhibitor p27Kip1 and the down-regulation of CDK1 (43).
SLOs are the site of antigen accumulation and lymphocyte priming. CCR7 and CXCR5/CXCL13 (see the record for ice) are essential for the development of SLOs [Figure 8; (44-46)]. Ccr7-/- mice develop most SLOs including spleen, Peyer’s Patches (PPs), and most lymph nodes (LNs), although loss of inguinal, popliteal, and parathymic LNs have been observed (45). The SLOs in the Ccr7-/- mice exhibit defective lymphocyte compartmentalization and disrupted architecture. CCR7 and CXCR5 exhibit overlapping functions in lymph node development through their expression on CD4+IL-7R+CD3− CD45+RORγt+ (see the record for chestnut) lymphoid tissue inducer (LTi) cells, which function in the development of SLOs (45;46). LTi cells are recruited to the site of SLO development. Lymphotoxin (LT) receptor ligand LTα1β2 expressed on the LTi cells ligates to the LT receptor (LTR; see the record for kama) expressed on stromal ‘organizer’ cells to mediate lymphoid tissue development and maintenance [reviewed in (34)]. After the development of SLOs, CCR7 mediates lymphocyte recruitment to LNs and PPs. Rolling naïve lymphocytes in the high endothelium venules (HEVs) within the cortex of LNs and PPs express CCR7, which detects CCL21 and/or CCL19 on the luminal surface of the HEVs. CCR7-associated signals after ligation result in L-selectin (see the record for dim_sum) and integrin activation, adhesion, and subsequent extravasation into the LN or PP [reviewed in (34)].
Within the SLOs, segregation of T and B cells is mediated by CCR7. The differential expression of CCR7 versus CXCR5 between naïve T and B cells regulates whether the cells locate to T cell areas or follicles, respectively [reviewed in (34)]. CCR7 also functions in regulation of antigen-engaged T cell recirculation and T cell survival in SLOs (47-49). CCR7 counteracts the lymphocyte egress signal mediated by sphingosine-1 phosphate receptor 1 (S1P1) (50). After naïve T cell activation by antigen, helper and cytotoxic T cells proliferate and differentiate. After antigen-specific T cell expansion, most effector cells undergo activation-induced cell death (AICD) to prevent autoimmunity, while others survive as memory T cells. CCL19/CCL21 expressed by stromal cells in the T cell zone of SLOs regulate CD4+ T-cell immune responses in SLOs by promoting AICD through a FasL-dependent pathway (see the records for cherry (Fas) and riogrande (Fasl)) (51).
CCR7/CCL21 regulates homeostatic trafficking of DCs to LNs (52-55), including the migration of small intestine lamina propria DCs (LP-DCs) to mesenteric LNs (56). CCR7-mediated activation of Jak3 is essential for DC maturation, migration, and function (57). Jak3-deficient (Jak3−/−) mice exhibit impaired bone marrow-derived macrophage migration towards CCL19 and CCL21 (57). Neutrophils also migrate in response to CCL19/CCL21 (16). Injection of Freund adjuvant induced recruitment of neutrophils to lymph nodes in wild-type mice, but not Ccr7-/- mice (16),
Treg cells maintain immune system homeostasis and regulate self-tolerance. CCR7 regulates Treg homing to the T cell zone in the LN and subsequent interaction between the Treg cells and antigen presenting cells [Figure 9; (58-60)]. Naive-like αE–CD25+ Treg cells from Ccr7-/- mice exhibited diminished rates of migration into LNs with a concomitant reduced capacity to suppress antigen-induced naïve T cell proliferation (61). CCR7 is required for the egress of effector T cells from tissues. CCR7 deficiency resulted in effector T cell accumulation in peripheral tissues including the skin, asthmatic lung, and peritoneal cavity (62-64). Loss of CCR7-dependent egress of effector T cells from peripheral tissues results in impaired resolution of peripheral immune responses that subsequently led to autoimmune lesions. CCR7 is also required for lymph node accumulation of central memory T cells (CD62L+CCR7hi) (65;66).
Ccr7-/- mice exhibit reduced or delayed adaptive immune responses, aberrant humoral immune responses, and diminished interactions between DCs and T cells in the LN paracortex [Figure 9; (44;67)]. CCR7 is not required in immune responses when B cells are able to provide sufficient antigen presentation such as in cases of various viral infections such as vesicular stromatitis virus (VSV), lymphochorio meningitis virus (LCMV) or vaccinia virus (VV) (68;69). CCR7 is required at multiple steps during DC migration from peripheral tissues to SLOs during inflammation (6). CCR7/CCL21 is required for DC entry into the LN as well as for entry into the LN paracortex from the subcabsular sinus (70). CCL19 promotes DC production of IL-1β, IL-12 and TNFα as well as the expression of co-stimulatory molecules CD40 and CD86 (71). Both CCL19 and CCL21 induce rapid endocytosis of antigen by DCs (72), promote mature DC survival (73;74), and CCL19 induces DC dendrite extension (75).
CCR7 is required for the T and B cell interactions that initiate a germinal center (GC) reaction. Antigen-inexperienced B cells exhibit a CXCR5+CCR7lo cell surface phenotype, which attracts and retains these cells within B cell follicles (13). After activation, antigen-stimulated B cells upregulate CCR7 expression (13), which facilitates their migration to and distribution along the T-B border (76). Increased CCR7 expression is also essential for T follicular helper (TFH) cell recruitment to the T-B border. TFH cell differentiation from naïve precursors is coupled with the loss of CCR7 and the induction of CXCR5, which subsequently promotes TFH cell migration into B cell follicles and GCs (77-79). Forced expression of CCR7 on T cells prevents their migration to follicular zones after immunization (79;80).
CCR7 also controls lymphocyte trafficking through nonlymphoid tissues. Ccr7-/- mice exhibit accumulation of lymphocytes in epithelial tissues (81). The gastrointestinal mucosal tissues of the Ccr7-/- mice exhibited the formation of lymphoid aggregates, which have topologic characteristics of LNs (81). The ectopic follicles have a high percentage of CD44hiCD62Llo effector memory T cells within the gastric lymphoid aggregates (81). In T-cell acute lymphoblastic leukemia (T-ALL), CCR7 functions as an adhesion signal that targets leukemic T cells into the central nervous system (82).
Ccr7-/- mice exhibit naïve T cell and DC deficiency, but the CD4+ T cell population in the peripheral blood, red pulp of the spleen, and bone marrow is expanded (44). Forster et al. determined that B and T cell migration into LNs and PPs as well as T cell migration into the splenic periarteriolar lymphoid sheath (PALS) was disrupted in the Ccr7-/- mice (44). In addition, B cells were retained in the PALS (44). The Ccr7-/- mice were unable to mount primary T cell responses and T-dependent (TD) antigen responses. Ccr7-/- mice immunized with T-independent type 2 (TI-2) antigens exhibited extrafollicular plasma cell responses, but persisting splenic germinal centers (83). Germinal center formation upon TI-2 and TD immunization were located in the PALS. The TI-2-induced GCs had peripheral rings of follicular DCs and T cells. Although the GC persisted, class-switching, affinity maturation, and memory B cell generation were not increased in the Ccr7-/- mice (83). Ccr7-/- mice exhibit increased susceptibility to streptozotocin-induced diabetes, spontaneous chronic autoimmune renal disease (84), and spontaneous autoimmune gastritis with a concomitant metaplasia of the gastric mucosa and formation of tertiary lymphoid organs at mucosal sites (85). Similar to the Ccr7-/- mice, the lanzhou mice exhibit an expanded population of CD4+ T cells in the peripheral blood, indicating loss of CCR7lanzhou function. Other immune-related phenotypes (e.g., diminished TD or TI responses) were not observed in the lanzhou mice, indicating that CCR7lanzhou may retain some residual function.
1) 94°C 2:00
The following sequence of 557 nucleotides is amplified (chromosome 11, - strand):
1 cctatgcatc agcattgacc gctacgtagc catcgtccag gccgtgtcgg ctcatcgcca
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.
1. Adzhubei, I. A., Schmidt, S., Peshkin, L., Ramensky, V. E., Gerasimova, A., Bork, P., Kondrashov, A. S., and Sunyaev, S. R. (2010) A Method and Server for Predicting Damaging Missense Mutations. Nat Methods. 7, 248-249.
2. Birkenbach, M., Josefsen, K., Yalamanchili, R., Lenoir, G., and Kieff, E. (1993) Epstein-Barr Virus-Induced Genes: First Lymphocyte-Specific G Protein-Coupled Peptide Receptors. J Virol. 67, 2209-2220.
3. Wettschureck, N., and Offermanns, S. (2005) Mammalian G Proteins and their Cell Type Specific Functions. Physiol Rev. 85, 1159-1204.
4. Constantin, G., Majeed, M., Giagulli, C., Piccio, L., Kim, J. Y., Butcher, E. C., and Laudanna, C. (2000) Chemokines Trigger Immediate beta2 Integrin Affinity and Mobility Changes: Differential Regulation and Roles in Lymphocyte Arrest Under Flow. Immunity. 13, 759-769.
5. Stein, J. V., Soriano, S. F., M'rini, C., Nombela-Arrieta, C., de Buitrago, G. G., Rodriguez-Frade, J. M., Mellado, M., Girard, J. P., and Martinez-A, C. (2003) CCR7-Mediated Physiological Lymphocyte Homing Involves Activation of a Tyrosine Kinase Pathway. Blood. 101, 38-44.
6. Iijima, N., Yanagawa, Y., Clingan, J. M., and Onoe, K. (2005) CCR7-Mediated c-Jun N-Terminal Kinase Activation Regulates Cell Migration in Mature Dendritic Cells. Int Immunol. 17, 1201-1212.
7. Misslitz, A., Pabst, O., Hintzen, G., Ohl, L., Kremmer, E., Petrie, H. T., and Forster, R. (2004) Thymic T Cell Development and Progenitor Localization Depend on CCR7. J Exp Med. 200, 481-491.
8. Sallusto, F., Lenig, D., Mackay, C. R., and Lanzavecchia, A. (1998) Flexible Programs of Chemokine Receptor Expression on Human Polarized T Helper 1 and 2 Lymphocytes. J Exp Med. 187, 875-883.
9. Sallusto, F., Lenig, D., Forster, R., Lipp, M., and Lanzavecchia, A. (1999) Two Subsets of Memory T Lymphocytes with Distinct Homing Potentials and Effector Functions. Nature. 401, 708-712.
10. Sallusto, F., Kremmer, E., Palermo, B., Hoy, A., Ponath, P., Qin, S., Forster, R., Lipp, M., and Lanzavecchia, A. (1999) Switch in Chemokine Receptor Expression upon TCR Stimulation Reveals Novel Homing Potential for Recently Activated T Cells. Eur J Immunol. 29, 2037-2045.
11. Campbell, J. J., Murphy, K. E., Kunkel, E. J., Brightling, C. E., Soler, D., Shen, Z., Boisvert, J., Greenberg, H. B., Vierra, M. A., Goodman, S. B., Genovese, M. C., Wardlaw, A. J., Butcher, E. C., and Wu, L. (2001) CCR7 Expression and Memory T Cell Diversity in Humans. J Immunol. 166, 877-884.
12. Szanya, V., Ermann, J., Taylor, C., Holness, C., and Fathman, C. G. (2002) The Subpopulation of CD4+CD25+ Splenocytes that Delays Adoptive Transfer of Diabetes Expresses L-Selectin and High Levels of CCR7. J Immunol. 169, 2461-2465.
13. Reif, K., Ekland, E. H., Ohl, L., Nakano, H., Lipp, M., Forster, R., and Cyster, J. G. (2002) Balanced Responsiveness to Chemoattractants from Adjacent Zones Determines B-Cell Position. Nature. 416, 94-99.
14. Sallusto, F., Schaerli, P., Loetscher, P., Schaniel, C., Lenig, D., Mackay, C. R., Qin, S., and Lanzavecchia, A. (1998) Rapid and Coordinated Switch in Chemokine Receptor Expression during Dendritic Cell Maturation. Eur J Immunol. 28, 2760-2769.
15. Ato, M., Nakano, H., Kakiuchi, T., and Kaye, P. M. (2004) Localization of Marginal Zone Macrophages is Regulated by C-C Chemokine Ligands 21/19. J Immunol. 173, 4815-4820.
16. Beauvillain, C., Cunin, P., Doni, A., Scotet, M., Jaillon, S., Loiry, M. L., Magistrelli, G., Masternak, K., Chevailler, A., Delneste, Y., and Jeannin, P. (2011) CCR7 is Involved in the Migration of Neutrophils to Lymph Nodes. Blood. 117, 1196-1204.
17. Gomez-Nicola, D., Pallas-Bazarra, N., Valle-Argos, B., and Nieto-Sampedro, M. (2010) CCR7 is Expressed in Astrocytes and Upregulated After an Inflammatory Injury. J Neuroimmunol. 227, 87-92.
18. Shields, J. D., Fleury, M. E., Yong, C., Tomei, A. A., Randolph, G. J., and Swartz, M. A. (2007) Autologous Chemotaxis as a Mechanism of Tumor Cell Homing to Lymphatics Via Interstitial Flow and Autocrine CCR7 Signaling. Cancer Cell. 11, 526-538.
19. Kerdiles, Y. M., Beisner, D. R., Tinoco, R., Dejean, A. S., Castrillon, D. H., DePinho, R. A., and Hedrick, S. M. (2009) Foxo1 Links Homing and Survival of Naive T Cells by Regulating L-Selectin, CCR7 and Interleukin 7 Receptor. Nat Immunol. 10, 176-184.
20. Bajana, S., Roach, K., Turner, S., Paul, J., and Kovats, S. (2012) IRF4 Promotes Cutaneous Dendritic Cell Migration to Lymph Nodes during Homeostasis and Inflammation. J Immunol. 189, 3368-3377.
21. Scandella, E., Men, Y., Gillessen, S., Forster, R., and Groettrup, M. (2002) Prostaglandin E2 is a Key Factor for CCR7 Surface Expression and Migration of Monocyte-Derived Dendritic Cells. Blood. 100, 1354-1361.
22. Scandella, E., Men, Y., Legler, D. F., Gillessen, S., Prikler, L., Ludewig, B., and Groettrup, M. (2004) CCL19/CCL21-Triggered Signal Transduction and Migration of Dendritic Cells Requires Prostaglandin E2. Blood. 103, 1595-1601.
23. Muthuswamy, R., Mueller-Berghaus, J., Haberkorn, U., Reinhart, T. A., Schadendorf, D., and Kalinski, P. (2010) PGE(2) Transiently Enhances DC Expression of CCR7 but Inhibits the Ability of DCs to Produce CCL19 and Attract Naive T Cells. Blood. 116, 1454-1459.
24. Kim, C. H., Pelus, L. M., White, J. R., and Broxmeyer, H. E. (1998) Differential Chemotactic Behavior of Developing T Cells in Response to Thymic Chemokines. Blood. 91, 4434-4443.
25. Campbell, J. J., Pan, J., and Butcher, E. C. (1999) Cutting Edge: Developmental Switches in Chemokine Responses during T Cell Maturation. J Immunol. 163, 2353-2357.
26. Adachi, S., Kuwata, T., Miyaike, M., and Iwata, M. (2001) Induction of CCR7 Expression in Thymocytes Requires both ERK Signal and Ca(2+) Signal. Biochem Biophys Res Commun. 288, 1188-1193.
27. Yu, C. R., Mahdi, R. M., Liu, X., Zhang, A., Naka, T., Kishimoto, T., and Egwuagu, C. E. (2008) SOCS1 Regulates CCR7 Expression and Migration of CD4+ T Cells into Peripheral Tissues. J Immunol. 181, 1190-1198.
28. Ploix, C., Lo, D., and Carson, M. J. (2001) A Ligand for the Chemokine Receptor CCR7 can Influence the Homeostatic Proliferation of CD4 T Cells and Progression of Autoimmunity. J Immunol. 167, 6724-6730.
29. Yoshida, R., Imai, T., Hieshima, K., Kusuda, J., Baba, M., Kitaura, M., Nishimura, M., Kakizaki, M., Nomiyama, H., and Yoshie, O. (1997) Molecular Cloning of a Novel Human CC Chemokine EBI1-Ligand Chemokine that is a Specific Functional Ligand for EBI1, CCR7. J Biol Chem. 272, 13803-13809.
30. Yoshida, R., Nagira, M., Kitaura, M., Imagawa, N., Imai, T., and Yoshie, O. (1998) Secondary Lymphoid-Tissue Chemokine is a Functional Ligand for the CC Chemokine Receptor CCR7. J Biol Chem. 273, 7118-7122.
31. Schumann, K., Lammermann, T., Bruckner, M., Legler, D. F., Polleux, J., Spatz, J. P., Schuler, G., Forster, R., Lutz, M. B., Sorokin, L., and Sixt, M. (2010) Immobilized Chemokine Fields and Soluble Chemokine Gradients Cooperatively Shape Migration Patterns of Dendritic Cells. Immunity. 32, 703-713.
32. Bardi, G., Lipp, M., Baggiolini, M., and Loetscher, P. (2001) The T Cell Chemokine Receptor CCR7 is Internalized on Stimulation with ELC, but Not with SLC. Eur J Immunol. 31, 3291-3297.
33. Kohout, T. A., Nicholas, S. L., Perry, S. J., Reinhart, G., Junger, S., and Struthers, R. S. (2004) Differential Desensitization, Receptor Phosphorylation, Beta-Arrestin Recruitment, and ERK1/2 Activation by the Two Endogenous Ligands for the CC Chemokine Receptor 7. J Biol Chem. 279, 23214-23222.
34. Comerford, I., Harata-Lee, Y., Bunting, M. D., Gregor, C., Kara, E. E., and McColl, S. R. (2013) A Myriad of Functions and Complex Regulation of the CCR7/CCL19/CCL21 Chemokine Axis in the Adaptive Immune System. Cytokine Growth Factor Rev. 24, 269-283.
35. Calderon, L., and Boehm, T. (2011) Three Chemokine Receptors Cooperatively Regulate Homing of Hematopoietic Progenitors to the Embryonic Mouse Thymus. Proc Natl Acad Sci U S A. 108, 7517-7522.
36. Liu, C., Saito, F., Liu, Z., Lei, Y., Uehara, S., Love, P., Lipp, M., Kondo, S., Manley, N., and Takahama, Y. (2006) Coordination between CCR7- and CCR9-Mediated Chemokine Signals in Prevascular Fetal Thymus Colonization. Blood. 108, 2531-2539.
37. Bai, Z., Hayasaka, H., Kobayashi, M., Li, W., Guo, Z., Jang, M. H., Kondo, A., Choi, B. I., Iwakura, Y., and Miyasaka, M. (2009) CXC Chemokine Ligand 12 Promotes CCR7-Dependent Naive T Cell Trafficking to Lymph Nodes and Peyer's Patches. J Immunol. 182, 1287-1295.
38. Ricart, B. G., John, B., Lee, D., Hunter, C. A., and Hammer, D. A. (2011) Dendritic Cells Distinguish Individual Chemokine Signals through CCR7 and CXCR4. J Immunol. 186, 53-61.
39. Ueno, T., Saito, F., Gray, D. H., Kuse, S., Hieshima, K., Nakano, H., Kakiuchi, T., Lipp, M., Boyd, R. L., and Takahama, Y. (2004) CCR7 Signals are Essential for Cortex-Medulla Migration of Developing Thymocytes. J Exp Med. 200, 493-505.
40. Davalos-Misslitz, A. C., Worbs, T., Willenzon, S., Bernhardt, G., and Forster, R. (2007) Impaired Responsiveness to T-Cell Receptor Stimulation and Defective Negative Selection of Thymocytes in CCR7-Deficient Mice. Blood. 110, 4351-4359.
41. Kwan, J., and Killeen, N. (2004) CCR7 Directs the Migration of Thymocytes into the Thymic Medulla. J Immunol. 172, 3999-4007.
42. Nitta, T., Nitta, S., Lei, Y., Lipp, M., and Takahama, Y. (2009) CCR7-Mediated Migration of Developing Thymocytes to the Medulla is Essential for Negative Selection to Tissue-Restricted Antigens. Proc Natl Acad Sci U S A. 106, 17129-17133.
43. Ziegler, E., Oberbarnscheidt, M., Bulfone-Paus, S., Forster, R., Kunzendorf, U., and Krautwald, S. (2007) CCR7 Signaling Inhibits T Cell Proliferation. J Immunol. 179, 6485-6493.
44. Forster, R., Schubel, A., Breitfeld, D., Kremmer, E., Renner-Muller, I., Wolf, E., and Lipp, M. (1999) CCR7 Coordinates the Primary Immune Response by Establishing Functional Microenvironments in Secondary Lymphoid Organs. Cell. 99, 23-33.
45. Ohl, L., Henning, G., Krautwald, S., Lipp, M., Hardtke, S., Bernhardt, G., Pabst, O., and Forster, R. (2003) Cooperating Mechanisms of CXCR5 and CCR7 in Development and Organization of Secondary Lymphoid Organs. J Exp Med. 197, 1199-1204.
46. Luther, S. A., Ansel, K. M., and Cyster, J. G. (2003) Overlapping Roles of CXCL13, Interleukin 7 Receptor Alpha, and CCR7 Ligands in Lymph Node Development. J Exp Med. 197, 1191-1198.
47. Okada, T., and Cyster, J. G. (2007) CC Chemokine Receptor 7 Contributes to Gi-Dependent T Cell Motility in the Lymph Node. J Immunol. 178, 2973-2978.
48. Worbs, T., Mempel, T. R., Bolter, J., von Andrian, U. H., and Forster, R. (2007) CCR7 Ligands Stimulate the Intranodal Motility of T Lymphocytes in Vivo. J Exp Med. 204, 489-495.
49. Link, A., Vogt, T. K., Favre, S., Britschgi, M. R., Acha-Orbea, H., Hinz, B., Cyster, J. G., and Luther, S. A. (2007) Fibroblastic Reticular Cells in Lymph Nodes Regulate the Homeostasis of Naive T Cells. Nat Immunol. 8, 1255-1265.
50. Pham, T. H., Okada, T., Matloubian, M., Lo, C. G., and Cyster, J. G. (2008) S1P1 Receptor Signaling Overrides Retention Mediated by G Alpha i-Coupled Receptors to Promote T Cell Egress. Immunity. 28, 122-133.
51. Yasuda, T., Kuwabara, T., Nakano, H., Aritomi, K., Onodera, T., Lipp, M., Takahama, Y., and Kakiuchi, T. (2007) Chemokines CCL19 and CCL21 Promote Activation-Induced Cell Death of Antigen-Responding T Cells. Blood. 109, 449-456.
52. Ohl, L., Mohaupt, M., Czeloth, N., Hintzen, G., Kiafard, Z., Zwirner, J., Blankenstein, T., Henning, G., and Forster, R. (2004) CCR7 Governs Skin Dendritic Cell Migration Under Inflammatory and Steady-State Conditions. Immunity. 21, 279-288.
53. Seth, S., Oberdorfer, L., Hyde, R., Hoff, K., Thies, V., Worbs, T., Schmitz, S., and Forster, R. (2011) CCR7 Essentially Contributes to the Homing of Plasmacytoid Dendritic Cells to Lymph Nodes Under Steady-State as Well as Inflammatory Conditions. J Immunol. 186, 3364-3372.
54. Britschgi, M. R., Favre, S., and Luther, S. A. (2010) CCL21 is Sufficient to Mediate DC Migration, Maturation and Function in the Absence of CCL19. Eur J Immunol. 40, 1266-1271.
55. Gunn, M. D., Kyuwa, S., Tam, C., Kakiuchi, T., Matsuzawa, A., Williams, L. T., and Nakano, H. (1999) Mice Lacking Expression of Secondary Lymphoid Organ Chemokine have Defects in Lymphocyte Homing and Dendritic Cell Localization. J Exp Med. 189, 451-460.
56. Jang, M. H., Sougawa, N., Tanaka, T., Hirata, T., Hiroi, T., Tohya, K., Guo, Z., Umemoto, E., Ebisuno, Y., Yang, B. G., Seoh, J. Y., Lipp, M., Kiyono, H., and Miyasaka, M. (2006) CCR7 is Critically Important for Migration of Dendritic Cells in Intestinal Lamina Propria to Mesenteric Lymph Nodes. J Immunol. 176, 803-810.
57. Rivas-Caicedo, A., Soldevila, G., Fortoul, T. I., Castell-Rodriguez, A., Flores-Romo, L., and Garcia-Zepeda, E. A. (2009) Jak3 is Involved in Dendritic Cell Maturation and CCR7-Dependent Migration. PLoS One. 4, e7066.
58. Schneider, M. A., Meingassner, J. G., Lipp, M., Moore, H. D., and Rot, A. (2007) CCR7 is Required for the in Vivo Function of CD4+ CD25+ Regulatory T Cells. J Exp Med. 204, 735-745.
59. Ueha, S., Yoneyama, H., Hontsu, S., Kurachi, M., Kitabatake, M., Abe, J., Yoshie, O., Shibayama, S., Sugiyama, T., and Matsushima, K. (2007) CCR7 Mediates the Migration of Foxp3+ Regulatory T Cells to the Paracortical Areas of Peripheral Lymph Nodes through High Endothelial Venules. J Leukoc Biol. 82, 1230-1238.
60. Smigiel, K. S., Richards, E., Srivastava, S., Thomas, K. R., Dudda, J. C., Klonowski, K. D., and Campbell, D. J. (2014) CCR7 Provides Localized Access to IL-2 and Defines Homeostatically Distinct Regulatory T Cell Subsets. J Exp Med. 211, 121-136.
61. Menning, A., Hopken, U. E., Siegmund, K., Lipp, M., Hamann, A., and Huehn, J. (2007) Distinctive Role of CCR7 in Migration and Functional Activity of Naive- and effector/memory-Like Treg Subsets. Eur J Immunol. 37, 1575-1583.
62. Debes, G. F., Arnold, C. N., Young, A. J., Krautwald, S., Lipp, M., Hay, J. B., and Butcher, E. C. (2005) Chemokine Receptor CCR7 Required for T Lymphocyte Exit from Peripheral Tissues. Nat Immunol. 6, 889-894.
63. Bromley, S. K., Thomas, S. Y., and Luster, A. D. (2005) Chemokine Receptor CCR7 Guides T Cell Exit from Peripheral Tissues and Entry into Afferent Lymphatics. Nat Immunol. 6, 895-901.
64. Hopken, U. E., Winter, S., Achtman, A. H., Kruger, K., and Lipp, M. (2010) CCR7 Regulates Lymphocyte Egress and Recirculation through Body Cavities. J Leukoc Biol. 87, 671-682.
65. Yang, L., Yu, Y., Kalwani, M., Tseng, T. W., and Baltimore, D. (2011) Homeostatic Cytokines Orchestrate the Segregation of CD4 and CD8 Memory T-Cell Reservoirs in Mice. Blood. 118, 3039-3050.
66. Scimone, M. L., Felbinger, T. W., Mazo, I. B., Stein, J. V., Von Andrian, U. H., and Weninger, W. (2004) CXCL12 Mediates CCR7-Independent Homing of Central Memory Cells, but Not Naive T Cells, in Peripheral Lymph Nodes. J Exp Med. 199, 1113-1120.
67. Mori, S., Nakano, H., Aritomi, K., Wang, C. R., Gunn, M. D., and Kakiuchi, T. (2001) Mice Lacking Expression of the Chemokines CCL21-Ser and CCL19 (Plt Mice) Demonstrate Delayed but Enhanced T Cell Immune Responses. J Exp Med. 193, 207-218.
68. Junt, T., Nakano, H., Dumrese, T., Kakiuchi, T., Odermatt, B., Zinkernagel, R. M., Hengartner, H., and Ludewig, B. (2002) Antiviral Immune Responses in the Absence of Organized Lymphoid T Cell Zones in plt/plt Mice. J Immunol. 168, 6032-6040.
69. Junt, T., Scandella, E., Forster, R., Krebs, P., Krautwald, S., Lipp, M., Hengartner, H., and Ludewig, B. (2004) Impact of CCR7 on Priming and Distribution of Antiviral Effector and Memory CTL. J Immunol. 173, 6684-6693.
70. Braun, A., Worbs, T., Moschovakis, G. L., Halle, S., Hoffmann, K., Bolter, J., Munk, A., and Forster, R. (2011) Afferent Lymph-Derived T Cells and DCs use Different Chemokine Receptor CCR7-Dependent Routes for Entry into the Lymph Node and Intranodal Migration. Nat Immunol. 12, 879-887.
71. Marsland, B. J., Battig, P., Bauer, M., Ruedl, C., Lassing, U., Beerli, R. R., Dietmeier, K., Ivanova, L., Pfister, T., Vogt, L., Nakano, H., Nembrini, C., Saudan, P., Kopf, M., and Bachmann, M. F. (2005) CCL19 and CCL21 Induce a Potent Proinflammatory Differentiation Program in Licensed Dendritic Cells. Immunity. 22, 493-505.
72. Yanagawa, Y., and Onoe, K. (2003) CCR7 Ligands Induce Rapid Endocytosis in Mature Dendritic Cells with Concomitant Up-Regulation of Cdc42 and Rac Activities. Blood. 101, 4923-4929.
73. Sanchez-Sanchez, N., Riol-Blanco, L., de la Rosa, G., Puig-Kroger, A., Garcia-Bordas, J., Martin, D., Longo, N., Cuadrado, A., Cabanas, C., Corbi, A. L., Sanchez-Mateos, P., and Rodriguez-Fernandez, J. L. (2004) Chemokine Receptor CCR7 Induces Intracellular Signaling that Inhibits Apoptosis of Mature Dendritic Cells. Blood. 104, 619-625.
74. Escribano, C., Delgado-Martin, C., and Rodriguez-Fernandez, J. L. (2009) CCR7-Dependent Stimulation of Survival in Dendritic Cells Involves Inhibition of GSK3beta. J Immunol. 183, 6282-6295.
75. Yanagawa, Y., and Onoe, K. (2002) CCL19 Induces Rapid Dendritic Extension of Murine Dendritic Cells. Blood. 100, 1948-1956.
76. Gatto, D., Wood, K., and Brink, R. (2011) EBI2 Operates Independently of but in Cooperation with CXCR5 and CCR7 to Direct B Cell Migration and Organization in Follicles and the Germinal Center. J Immunol. 187, 4621-4628.
77. Arnold, C. N., Campbell, D. J., Lipp, M., and Butcher, E. C. (2007) The Germinal Center Response is Impaired in the Absence of T Cell-Expressed CXCR5. Eur J Immunol. 37, 100-109.
78. Hardtke, S., Ohl, L., and Forster, R. (2005) Balanced Expression of CXCR5 and CCR7 on Follicular T Helper Cells Determines their Transient Positioning to Lymph Node Follicles and is Essential for Efficient B-Cell Help. Blood. 106, 1924-1931.
79. Haynes, N. M., Allen, C. D., Lesley, R., Ansel, K. M., Killeen, N., and Cyster, J. G. (2007) Role of CXCR5 and CCR7 in Follicular Th Cell Positioning and Appearance of a Programmed Cell Death Gene-1high Germinal Center-Associated Subpopulation. J Immunol. 179, 5099-5108.
80. Randolph, D. A., Huang, G., Carruthers, C. J., Bromley, L. E., and Chaplin, D. D. (1999) The Role of CCR7 in TH1 and TH2 Cell Localization and Delivery of B Cell Help in Vivo. Science. 286, 2159-2162.
81. Hopken, U. E., Wengner, A. M., Loddenkemper, C., Stein, H., Heimesaat, M. M., Rehm, A., and Lipp, M. (2007) CCR7 Deficiency Causes Ectopic Lymphoid Neogenesis and Disturbed Mucosal Tissue Integrity. Blood. 109, 886-895.
82. Buonamici, S., Trimarchi, T., Ruocco, M. G., Reavie, L., Cathelin, S., Mar, B. G., Klinakis, A., Lukyanov, Y., Tseng, J. C., Sen, F., Gehrie, E., Li, M., Newcomb, E., Zavadil, J., Meruelo, D., Lipp, M., Ibrahim, S., Efstratiadis, A., Zagzag, D., Bromberg, J. S., Dustin, M. L., and Aifantis, I. (2009) CCR7 Signalling as an Essential Regulator of CNS Infiltration in T-Cell Leukaemia. Nature. 459, 1000-1004.
83. Achtman, A. H., Hopken, U. E., Bernert, C., and Lipp, M. (2009) CCR7-Deficient Mice Develop Atypically Persistent Germinal Centers in Response to Thymus-Independent Type 2 Antigens. J Leukoc Biol. 85, 409-417.
84. Davalos-Misslitz, A. C., Rieckenberg, J., Willenzon, S., Worbs, T., Kremmer, E., Bernhardt, G., and Forster, R. (2007) Generalized Multi-Organ Autoimmunity in CCR7-Deficient Mice. Eur J Immunol. 37, 613-622.
|Science Writers||Anne Murray|
|Authors||Ming Zeng, Bruce Beutler|