C-C chemokine receptor type 7

Last updated
CCR7
CCR7 receptor.png
Identifiers
Aliases CCR7 , BLR2, CC-CKR-7, CCR-7, CD197, CDw197, CMKBR7, EBI1, C-C motif chemokine receptor 7
External IDs OMIM: 600242 MGI: 103011 HomoloGene: 1387 GeneCards: CCR7
Orthologs
SpeciesHumanMouse
Entrez

1236

12775

Ensembl

ENSG00000126353

ENSMUSG00000037944

UniProt

P32248

P47774

RefSeq (mRNA)

NM_001838
NM_001301714
NM_001301716
NM_001301717
NM_001301718

Contents

NM_001301713
NM_007719

RefSeq (protein)

NP_001288643
NP_001288645
NP_001288646
NP_001288647
NP_001829

NP_001288642
NP_031745

Location (UCSC) Chr 17: 40.55 – 40.57 Mb Chr 11: 99.04 – 99.05 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

C-C chemokine receptor type 7 is a protein that in humans is encoded by the CCR7 gene. [5] Two ligands have been identified for this receptor: the chemokines (C-C motif) ligand 19 (CCL19/ELC) and (C-C motif) ligand 21 (CCL21). [6] The ligands have similar affinity for the receptor, though CCL19 has been shown to induce internalisation of CCR7 and desensitisation of the cell to CCL19/CCL21 signals. [7] CCR7 is a transmembrane protein with 7 transmembrane domains, which is coupled with heterotrimeric G proteins, which transduce the signal downstream through various signalling cascades. The main function of the receptor is to guide immune cells to immune organs (lymph nodes, thymus, spleen) by detecting specific chemokines, which these tissues secrete. [7]

CCR7 has also recently been designated CD197 (cluster of differentiation 197).

Function

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. [8] As stated above, the receptor guides immune cells to immune organs such as lymph nodes, which is needed for the development of both resistance and tolerance, but it is also important for development of T cells in thymus. The receptor is expressed mostly on adaptive immune cell types, namely thymocytes, naive T and B cells, regulatory T cells, central memory lymphocytes, but also dendritic cells. [7] CCR7 has been shown to stimulate dendritic cell maturation. CCR7 is also involved in homing of T cells to various secondary lymphoid organs such as lymph nodes and the spleen as well as trafficking of T cells within the spleen. [8]

CCR7 in dendritic cells

CCR7´s function is best studied in dendritic cells. Their activation in peripheral tissues induces CCR7 expression on the cell's surface, which recognize CCL19 and CCL21 produced in the Lymph node and increases dendritic cell expression of co-stimulation molecules (B7), and MHC class I or MHC class II. [9] CCR7 signalling was also found to affect chemotaxis, actin dynamics but also survival of dendritic cells, though all of the mentioned functions are induced by different independent signalling pathways. [10] Chemotaxis is regulated by MAPK pathway and surprisignly is independent of CCR7 signalling pathway regulating actin dynamics. Executive components of this cascade are kinases MEK1/2, ERK1/2, p38, JNK and perhaps others. The executive kinases phosphorylate transcription factors and other regulators thereby changing expresison profile of the cell. [10] Increased cellular survival upon CCR7 ligation stems from both pro-apoptotic molecules inhibition and survival promoting proteins stimulation as the receptor is known to activate the PI3K/AKT/mTOR pathway The effector molecules of this pathway are mTOR and NFkB, collectively the effect is exerted via anti-apoptotic Bcl2 proteins expression and inhibition of pro-apoptotic proteins GSK3B, FOXO1/3 and 4EBP1. CCR7 affects cellular actin dynamics via the RhoA/cofilin pathway. [10]

Influence of CCR7 on central tolerance

CCR7 has been shown to be important for the selection process of T cells in thymus and its morphology formation. Experiments in mouse models have shown that mice lacking CCR7 had fewer thymocytes during development and more frequent autoimmune disorders. It is believed, that CCR7 takes part in homing of lymphoid progenitors to thymus, but also in thymocyte transition from thymic cortex to medulla. [7] Once double negative thymocyte (first step of T cell development) undergoes positive selection, it becomes double positive (expressing both CD4 and CD8 coreceptors) and starts to express CCR7, which guides it to thymic medulla, where negative selection takes place. ccr7 knockout mice have leaky negative selection are prone autoimmune disorders. The mechanism is thought to be both thymus morphology disruption and insufficient T cell receptor stimulation [7] It must however be noted that CCR7 affects not only central tolerance, but also peripheral tolerance by allowing homing of tolerogenic dendritic cells to lymph nodes. [11]

Clinical significance

CCR7 is expressed by various cancer cells, such as nonsmall lung cancer, gastric cancer and oesophageal cancer. [12] [13] [14] Expression of CCR7, usually with VEGF family proteins, by cancer cells is linked with metastasis and generally poorer prognosis. [15] Multiple mechanisms through which CCR7 expression changes the prognosis of cancer patients have been discovered. [16] As described above on the example of dendritic cells, CCR7 enhances survival of the cell and enables it to migrate following CCL19/CCL21 gradient, which leads to lymph nodes, in addition to that it has been shown that CCR7 ligation promotes EMT transition, which is cruicial for metastasis, as it allows cells to detach and migrate. Also CCR7 signalling induces VEGF-C and VEGF-D molecules, which promote lymphoneogenesis around the tumour. [16]

Related Research Articles

<span class="mw-page-title-main">L-selectin</span> Mammalian protein found in Homo sapiens

L-selectin, also known as CD62L, is a cell adhesion molecule found on the cell surface of leukocytes, and the blastocyst. It is coded for in the human by the SELL gene. L-selectin belongs to the selectin family of proteins, which recognize sialylated carbohydrate groups containing a Sialyl LewisX (sLeX) determinant. L-selectin plays an important role in both the innate and adaptive immune responses by facilitating leukocyte-endothelial cell adhesion events. These tethering interactions are essential for the trafficking of monocytes and neutrophils into inflamed tissue as well as the homing of lymphocytes to secondary lymphoid organs. L-selectin is also expressed by lymphoid primed hematopoietic stem cells and may participate in the migration of these stem cells to the primary lymphoid organs. In addition to its function in the immune response, L-selectin is expressed on embryonic cells and facilitates the attachment of the blastocyst to the endometrial endothelium during human embryo implantation.

<span class="mw-page-title-main">Macrophage inflammatory protein</span> Protein family

Macrophage Inflammatory Proteins (MIP) belong to the family of chemotactic cytokines known as chemokines. In humans, there are two major forms, MIP-1α and MIP-1β, renamed CCL3 and CCL4 respectively, since 2000. However, other names are sometimes encountered in older literature, such as LD78α, AT 464.1 and GOS19-1 for human CCL3 and AT 744, Act-2, LAG-1, HC21 and G-26 for human CCL4. Other macrophage inflammatory proteins include MIP-2, MIP-3 and MIP-5.

<span class="mw-page-title-main">CCL20</span> Mammalian protein found in Homo sapiens

Chemokine ligand 20 (CCL20) or liver activation regulated chemokine (LARC) or Macrophage Inflammatory Protein-3 (MIP3A) is a small cytokine belonging to the CC chemokine family. It is strongly chemotactic for lymphocytes and weakly attracts neutrophils. CCL20 is implicated in the formation and function of mucosal lymphoid tissues via chemoattraction of lymphocytes and dendritic cells towards the epithelial cells surrounding these tissues. CCL20 elicits its effects on its target cells by binding and activating the chemokine receptor CCR6.

<span class="mw-page-title-main">CCL18</span> Mammalian protein found in Homo sapiens

Chemokine ligand 18 (CCL18) is a small cytokine belonging to the CC chemokine family. The functions of CCL18 have been well studied in laboratory settings, however the physiological effects of the molecule in living organisms have been difficult to characterize because there is no similar protein in rodents that can be studied. The receptor for CCL18 has been identified in humans only recently, which will help scientists understand the molecule's role in the body.

<span class="mw-page-title-main">CCL21</span> Mammalian protein found in Homo sapiens

Chemokine ligand 21 (CCL21) is a small cytokine belonging to the CC chemokine family. This chemokine is also known as 6Ckine, exodus-2, and secondary lymphoid-tissue chemokine (SLC). CCL21 elicits its effects by binding to a cell surface chemokine receptor known as CCR7. The main function of CCL21 is to guide CCR7 expressing leukocytes to the secondary lymphoid organs, such as lymph nodes and Peyer´s patches.

<span class="mw-page-title-main">CCL19</span> Mammalian protein found in Homo sapiens

Chemokine ligand 19 (CCL19) is a protein that in humans is encoded by the CCL19 gene.

CC chemokine receptors are integral membrane proteins that specifically bind and respond to cytokines of the CC chemokine family. They represent one subfamily of chemokine receptors, a large family of G protein-linked receptors that are known as seven transmembrane (7-TM) proteins since they span the cell membrane seven times. To date, ten true members of the CC chemokine receptor subfamily have been described. These are named CCR1 to CCR10 according to the IUIS/WHO Subcommittee on Chemokine Nomenclature.

<span class="mw-page-title-main">CXCR5</span> Mammalian protein found in Homo sapiens

C-X-C chemokine receptor type 5 (CXC-R5) also known as CD185 or Burkitt lymphoma receptor 1 (BLR1) is a G protein-coupled seven transmembrane receptor for chemokine CXCL13 and belongs to the CXC chemokine receptor family. It enables T cells to migrate to lymph node and the B cell zones. In humans, the CXC-R5 protein is encoded by the CXCR5 gene.

<span class="mw-page-title-main">C-C chemokine receptor type 6</span> Mammalian protein found in Homo sapiens

Chemokine receptor 6 also known as CCR6 is a CC chemokine receptor protein which in humans is encoded by the CCR6 gene. CCR6 has also recently been designated CD196. The gene is located on the long arm of Chromosome 6 (6q27) on the Watson (plus) strand. It is 139,737 bases long and encodes a protein of 374 amino acids.

<span class="mw-page-title-main">CD69</span> Human lectin protein

CD69 is a human transmembrane C-Type lectin protein encoded by the CD69 gene. It is an early activation marker that is expressed in hematopoietic stem cells, T cells, and many other cell types in the immune system. It is also implicated in T cell differentiation as well as lymphocyte retention in lymphoid organs.

<span class="mw-page-title-main">GPR183</span> Protein-coding gene in the species Homo sapiens

G-protein coupled receptor 183 also known as Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2) is a protein (GPCR) expressed on the surface of some immune cells, namely B cells and T cells; in humans it is encoded by the GPR183 gene. Expression of EBI2 is one critical mediator of immune cell localization within lymph nodes, responsible in part for the coordination of B cell, T cell, and dendritic cell movement and interaction following antigen exposure. EBI2 is a receptor for oxysterols. The most potent activator is 7α,25-dihydroxycholesterol (7α,25-OHC), with other oxysterols exhibiting varying affinities for the receptor. Oxysterol gradients drive chemotaxis, attracting the EBI2-expressing cells to locations of high ligand concentration. The GPR183 gene was identified due to its upregulation during Epstein-Barr virus infection of the Burkitt's lymphoma cell line BL41, hence its name: EBI2.

<span class="mw-page-title-main">CCR9</span> Protein-coding gene in the species Homo sapiens

C-C chemokine receptor type 9 is a protein that in humans is encoded by the CCR9 gene. This gene is mapped to the chemokine receptor gene cluster region. Two alternatively spliced transcript variants have been described.

<span class="mw-page-title-main">SLAMF1</span> Protein-coding gene in humans

Signaling lymphocytic activation molecule 1 is a protein that in humans is encoded by the SLAMF1 gene. Recently SLAMF1 has also been designated CD150.

<span class="mw-page-title-main">ICOSLG</span> Protein-coding gene in the species Homo sapiens

ICOS ligand is a protein that in humans is encoded by the ICOSLG gene located at chromosome 21. ICOSLG has also been designated as CD275.

<span class="mw-page-title-main">KLRB1</span> Protein-coding gene in humans

Killer cell lectin-like receptor subfamily B, member 1, also known as KLRB1, NKR-P1A or CD161, is a human gene.

<span class="mw-page-title-main">Lymphocyte-activation gene 3</span>

Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene. LAG3, which was discovered in 1990 and was designated CD223 after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000, is a cell surface molecule with diverse biological effects on T cell function but overall has an immune inhibitory effect. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. In soluble form it is also being developed as a cancer drug in its own right.

<span class="mw-page-title-main">CD200</span> Protein-coding gene in the species Homo sapiens

OX-2 membrane glycoprotein, also named CD200 is a human protein encoded by the CD200 gene. CD200 gene is in human located on chromosome 3 in proximity to genes encoding other B7 proteins CD80/CD86. In mice CD200 gene is on chromosome 16.

Chemorepulsion is the directional movement of a cell away from a substance. Of the two directional varieties of chemotaxis, chemoattraction has been studied to a much greater extent. Only recently have the key components of the chemorepulsive pathway been elucidated. The exact mechanism is still being investigated, and its constituents are currently being explored as likely candidates for immunotherapies.

Lymph node stromal cells are essential to the structure and function of the lymph node whose functions include: creating an internal tissue scaffold for the support of hematopoietic cells; the release of small molecule chemical messengers that facilitate interactions between hematopoietic cells; the facilitation of the migration of hematopoietic cells; the presentation of antigens to immune cells at the initiation of the adaptive immune system; and the homeostasis of lymphocyte numbers. Stromal cells originate from multipotent mesenchymal stem cells.

Gut-specific homing is the mechanism by which activated T cells and antibody-secreting cells (ASCs) are targeted to both inflamed and non-inflamed regions of the gut in order to provide an effective immune response. This process relies on the key interaction between the integrin α4β7 and the addressin MadCAM-1 on the surfaces of the appropriate cells. Additionally, this interaction is strengthened by the presence of CCR9, a chemokine receptor, which interacts with TECK. Vitamin A-derived retinoic acid regulates the expression of these cell surface proteins.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000126353 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000037944 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Birkenbach M, Josefsen K, Yalamanchili R, Lenoir G, Kieff E (April 1993). "Epstein-Barr virus-induced genes: first lymphocyte-specific G protein-coupled peptide receptors". Journal of Virology. 67 (4): 2209–2220. doi:10.1128/JVI.67.4.2209-2220.1993. PMC   240341 . PMID   8383238.
  6. ↑ F. Balkwill, Cancer and the Chemokine Network, Nature reviews, 2004
  7. 1 2 3 4 5 Alrumaihi F (2022). "The Multi-Functional Roles of CCR7 in Human Immunology and as a Promising Therapeutic Target for Cancer Therapeutics". Frontiers in Molecular Biosciences. 9: 834149. doi: 10.3389/fmolb.2022.834149 . PMC   9298655 . PMID   35874608.
  8. 1 2 Sharma N, Benechet AP, Lefrançois L, Khanna KM (December 2015). "CD8 T Cells Enter the Splenic T Cell Zones Independently of CCR7, but the Subsequent Expansion and Trafficking Patterns of Effector T Cells after Infection Are Dysregulated in the Absence of CCR7 Migratory Cues". Journal of Immunology. 195 (11): 5227–5236. doi:10.4049/jimmunol.1500993. PMC   4655190 . PMID   26500349.
  9. ↑ Riol-Blanco L, Sánchez-Sánchez N, Torres A, Tejedor A, Narumiya S, Corbí AL, et al. (April 2005). "The chemokine receptor CCR7 activates in dendritic cells two signaling modules that independently regulate chemotaxis and migratory speed". Journal of Immunology. 174 (7): 4070–4080. doi: 10.4049/jimmunol.174.7.4070 . PMID   15778365.
  10. 1 2 3 Rodríguez-Fernández JL, Criado-García O (2020). "The Chemokine Receptor CCR7 Uses Distinct Signaling Modules With Biased Functionality to Regulate Dendritic Cells". Frontiers in Immunology. 11: 528. doi: 10.3389/fimmu.2020.00528 . PMC   7174648 . PMID   32351499.
  11. ↑ Brandum EP, Jørgensen AS, Rosenkilde MM, Hjortø GM (August 2021). "Dendritic Cells and CCR7 Expression: An Important Factor for Autoimmune Diseases, Chronic Inflammation, and Cancer". International Journal of Molecular Sciences. 22 (15): 8340. doi: 10.3390/ijms22158340 . PMC   8348795 . PMID   34361107.
  12. ↑ Mashino K, Sadanaga N, Yamaguchi H, Tanaka F, Ohta M, Shibuta K, et al. (May 2002). "Expression of chemokine receptor CCR7 is associated with lymph node metastasis of gastric carcinoma". Cancer Research. 62 (10): 2937–2941. PMID   12019175.
  13. ↑ Takanami I (June 2003). "Overexpression of CCR7 mRNA in nonsmall cell lung cancer: correlation with lymph node metastasis". International Journal of Cancer. 105 (2): 186–189. doi: 10.1002/ijc.11063 . PMID   12673677. S2CID   1523901.
  14. ↑ Ding Y, Shimada Y, Maeda M, Kawabe A, Kaganoi J, Komoto I, et al. (August 2003). "Association of CC chemokine receptor 7 with lymph node metastasis of esophageal squamous cell carcinoma". Clinical Cancer Research. 9 (9): 3406–3412. PMID   12960129.
  15. ↑ Shields JD, Fleury ME, Yong C, Tomei AA, Randolph GJ, Swartz MA (June 2007). "Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling". Cancer Cell. 11 (6): 526–538. doi: 10.1016/j.ccr.2007.04.020 . PMID   17560334.
  16. 1 2 Salem A, Alotaibi M, Mroueh R, Basheer HA, Afarinkia K (January 2021). "CCR7 as a therapeutic target in Cancer". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1875 (1): 188499. doi:10.1016/j.bbcan.2020.188499. PMID   33385485. S2CID   230108218.

Further reading

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