CCL21

CCL21
Available structures PDB Ortholog search:PDBeRCSB List of PDB id codes 2L4N
Identifiers
Aliases	CCL21,6Ckine, CKb9, ECL, SCYA21, SLC, TCA4, C-C motif chemokine ligand 21
External IDs	OMIM:602737;MGI:1349183;HomoloGene:2247;GeneCards:CCL21;OMA:CCL21 - orthologs
Gene location (Human) Chr. Chromosome 9 (human) Band 9p13.3 Start 34,709,005bp End 34,710,136bp
Gene location (Mouse) Chr. Chromosome 4 (mouse) Band 4 A5|4 22.81 cM Start 42,772,860bp End 42,773,993bp
RNA expressionpattern Bgee Human Mouse(ortholog) Top expressed in lymph node right lobe of thyroid gland appendix left lobe of thyroid gland rectum gallbladder gastric mucosa mucosa of transverse colon right uterine tube upper lobe of left lung Top expressed in thymus spleen urinary bladder lip ovary lung esophagus uterus colon ileum More reference expression data BioGPS More reference expression data
Gene ontology Molecular function cytokine activity chemokine receptor binding CCR7 chemokine receptor binding chemokine activity CCR chemokine receptor binding protein binding Cellular component extracellular region extracellular space Biological process negative regulation of leukocyte tethering or rolling release of sequestered calcium ion into cytosol positive regulation of receptor-mediated endocytosis positive regulation of protein kinase B signaling positive regulation of cell motility positive regulation of actin filament polymerization monocyte chemotaxis activation of GTPase activity ruffle organization positive regulation of cell-matrix adhesion chemokine-mediated signaling pathway cellular response to tumor necrosis factor cell-cell signaling T cell costimulation cell maturation positive regulation of JNK cascade dendritic cell chemotaxis negative regulation of dendritic cell dendrite assembly positive regulation of phosphatidylinositol 3-kinase activity chemotaxis response to prostaglandin E positive regulation of dendritic cell antigen processing and presentation dendritic cell dendrite assembly positive regulation of pseudopodium assembly mesangial cell-matrix adhesion positive regulation of chemotaxis cellular response to interleukin-1 immune response establishment of T cell polarity positive regulation of ERK1 and ERK2 cascade positive regulation of glycoprotein biosynthetic process cellular response to interferon-gamma positive regulation of I-kappaB kinase/NF-kappaB signaling cell chemotaxis lymphocyte chemotaxis positive regulation of neutrophil chemotaxis positive regulation of cell adhesion mediated by integrin immunological synapse formation positive regulation of filopodium assembly positive regulation of T cell migration positive regulation of myeloid dendritic cell chemotaxis positive regulation of protein kinase activity inflammatory response antimicrobial humoral immune response mediated by antimicrobial peptide regulation of signaling receptor activity G protein-coupled receptor signaling pathway negative regulation of dendritic cell apoptotic process positive regulation of T cell chemotaxis neutrophil chemotaxis chemokine (C-C motif) ligand 21 signaling pathway positive regulation of GTPase activity cellular response to chemokine Sources:Amigo/QuickGO
Orthologs Species Human Mouse Entrez 6366 18829 Ensembl ENSG00000137077 ENSMUSG00000094686 UniProt O00585 P84444 RefSeq (mRNA) NM_002989 NM_011124 RefSeq (protein) NP_002980 NP_035254 Location (UCSC) Chr 9: 34.71 – 34.71 Mb Chr 4: 42.77 – 42.77 Mb PubMedsearch
Wikidata
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Chemokine (C-C motif) ligand 21(CCL21) is a smallcytokinebelonging to the CCchemokinefamily. This chemokine is also known as 6Ckine (because it has six conservedcysteineresidues instead of the four cysteines typical to chemokines), exodus-2, and secondary lymphoid-tissue chemokine (SLC).CCL21 elicits its effects by binding to a cell surfacechemokine receptorknown asCCR7.The main function of CCL21 is to guideCCR7expressingleukocytesto thesecondary lymphoid organs,such aslymph nodesandPeyer´s patches.

Gene

Thegenefor CCL21 is located on humanchromosome9.CCL21 is classified as a homeostaticchemokine,it is produced constitutively. However, its expression increases duringinflammation.

Protein structure

ChemokineCCL21 contains an extendedC-terminuswhich is not found inCCL19,another ligand ofCCR7.C-terminal tailis composed of 37amino acidsrich in positively charged residues and therefore, it has high affinity for negatively charged molecules of theextracellular matrix.The cleavage of theC-terminal tailby peptidases produces a soluble form of CCL21.The soluble CCL21 occurs also inphysiological conditions.It does not bind toextracellular matrixand therefore, its function differs from the function of the full-length CCL21.

Function

Migration to secondary lymphoid organs

Naïve T cellscirculate throughsecondary lymphoid organsuntil they encounter theantigen.CCL21 is achemokineinvolved in the recruitment ofT cellsintosecondary lymphoid organs.It is produced by lymphatic endothelial cells andlymph node stromal cells.Full-length CCL21 is bound toglycosaminoglycans,andendothelial cellsand it induces the chemotactic migration ofT cellsand thecell adhesioncaused byintegrinactivation.In contrast, the soluble CCL21 is not involved in the induction of thecell adhesion.AfterT cellsenter thelymph nodesthroughhigh endothelial venules,they are attracted to the T cell zone, where fibroblastic reticular cells are the abundant source of CCL21.

CCL21/CCR7interaction also plays a role in the migration ofdendritic cellsto thesecondary lymphoid organs.Dendritic cellsupregulate the expression ofCCR7during their maturation.CCL21 is bound to thelymphatic vesselsand attractsCCR7expressingdendritic cellsfrom peripheral tissues. Then they migrate along the chemokine gradient to thelymph nodewhere theypresent the antigentoT cells.Interactions betweendendritic cellsandT cellsare necessary for the initiation of theadaptive immune response.When CCL21 is not recognized by the cells (for example inCCR7-deficient mice), a delayed and reducedadaptive immune responseoccurs due to reduced interactions betweendendritic cellsandT cellsin thelymph nodes.Semi-maturedendritic cellsexpressCCR7in the absence of a danger signal. They use CCL21 chemokine gradient for the migration to thelymph nodeseven when there is noinflammationin the body, and they contribute toperipheral tolerance.

Othercellsusing chemokine CCL21 for the migration to thelymph nodesareB cells.However, they are less dependent on it in comparison toT cells.

T cell development in the thymus

CCL21/CCR7interaction plays a role in theT celldevelopment in thethymus.CCL21 is produced in the thymus medulla bymedullary thymic epithelial cells,and it attracts single positivethymocytesfrom the thymus cortex to the medulla, where they undergonegative selectionto delete autoreactivethymocytes.

External links

• HumanCCL21genome location andCCL21gene details page in theUCSC Genome Browser.

Further reading

• Nagira M, Imai T, Hieshima K, Kusuda J, Ridanpää M, Takagi S, et al. (August 1997)."Molecular cloning of a novel human CC chemokine secondary lymphoid-tissue chemokine that is a potent chemoattractant for lymphocytes and mapped to chromosome 9p13".The Journal of Biological Chemistry.272(31): 19518–19524.doi:10.1074/jbc.272.31.19518.PMID9235955.
• Hedrick JA, Zlotnik A (August 1997)."Identification and characterization of a novel beta chemokine containing six conserved cysteines".Journal of Immunology.159(4): 1589–1593.doi:10.4049/jimmunol.159.4.1589.PMID9257816.S2CID23429282.
• Hromas R, Kim CH, Klemsz M, Krathwohl M, Fife K, Cooper S, et al. (September 1997)."Isolation and characterization of Exodus-2, a novel C-C chemokine with a unique 37-amino acid carboxyl-terminal extension".Journal of Immunology.159(6): 2554–2558.doi:10.4049/jimmunol.159.6.2554.PMID9300671.S2CID33971251.
• Gunn MD, Tangemann K, Tam C, Cyster JG, Rosen SD, Williams LT (January 1998)."A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes".Proceedings of the National Academy of Sciences of the United States of America.95(1): 258–263.Bibcode:1998PNAS...95..258G.doi:10.1073/pnas.95.1.258.PMC18193.PMID9419363.
• Yoshida R, Nagira M, Kitaura M, Imagawa N, Imai T, Yoshie O (March 1998)."Secondary lymphoid-tissue chemokine is a functional ligand for the CC chemokine receptor CCR7".The Journal of Biological Chemistry.273(12): 7118–7122.doi:10.1074/jbc.273.12.7118.PMID9507024.
• Campbell JJ, Bowman EP, Murphy K, Youngman KR, Siani MA, Thompson DA, et al. (May 1998)."6-C-kine (SLC), a lymphocyte adhesion-triggering chemokine expressed by high endothelium, is an agonist for the MIP-3beta receptor CCR7".The Journal of Cell Biology.141(4): 1053–1059.doi:10.1083/jcb.141.4.1053.PMC2132769.PMID9585422.
• Jenh CH, Cox MA, Kaminski H, Zhang M, Byrnes H, Fine J, et al. (April 1999)."Cutting edge: species specificity of the CC chemokine 6Ckine signaling through the CXC chemokine receptor CXCR3: human 6Ckine is not a ligand for the human or mouse CXCR3 receptors".Journal of Immunology.162(7): 3765–3769.doi:10.4049/jimmunol.162.7.3765.PMID10201891.S2CID23946439.
• Gosling J, Dairaghi DJ, Wang Y, Hanley M, Talbot D, Miao Z, Schall TJ (March 2000)."Cutting edge: identification of a novel chemokine receptor that binds dendritic cell- and T cell-active chemokines including ELC, SLC, and TECK".Journal of Immunology.164(6): 2851–2856.doi:10.4049/jimmunol.164.6.2851.PMID10706668.
• Annunziato F, Romagnani P, Cosmi L, Beltrame C, Steiner BH, Lazzeri E, et al. (July 2000)."Macrophage-derived chemokine and EBI1-ligand chemokine attract human thymocytes in different stage of development and are produced by distinct subsets of medullary epithelial cells: possible implications for negative selection".Journal of Immunology.165(1): 238–246.doi:10.4049/jimmunol.165.1.238.PMID10861057.
• Hirose J, Kawashima H, Yoshie O, Tashiro K, Miyasaka M (February 2001)."Versican interacts with chemokines and modulates cellular responses".The Journal of Biological Chemistry.276(7): 5228–5234.doi:10.1074/jbc.M007542200.PMID11083865.
• Till KJ, Lin K, Zuzel M, Cawley JC (April 2002)."The chemokine receptor CCR7 and alpha4 integrin are important for migration of chronic lymphocytic leukemia cells into lymph nodes".Blood.99(8): 2977–2984.doi:10.1182/blood.V99.8.2977.PMID11929789.
• Grant AJ, Goddard S, Ahmed-Choudhury J, Reynolds G, Jackson DG, Briskin M, et al. (April 2002)."Hepatic expression of secondary lymphoid chemokine (CCL21) promotes the development of portal-associated lymphoid tissue in chronic inflammatory liver disease".The American Journal of Pathology.160(4): 1445–1455.doi:10.1016/S0002-9440(10)62570-9.PMC1867219.PMID11943728.
• Banas B, Wörnle M, Berger T, Nelson PJ, Cohen CD, Kretzler M, et al. (May 2002)."Roles of SLC/CCL21 and CCR7 in human kidney for mesangial proliferation, migration, apoptosis, and tissue homeostasis".Journal of Immunology.168(9): 4301–4307.doi:10.4049/jimmunol.168.9.4301.PMID11970971.
• Christopherson KW, Hood AF, Travers JB, Ramsey H, Hromas RA (February 2003)."Endothelial induction of the T-cell chemokine CCL21 in T-cell autoimmune diseases".Blood.101(3): 801–806.doi:10.1182/blood-2002-05-1586.PMID12393410.
• Stein JV, Soriano SF, M'rini C, Nombela-Arrieta C, de Buitrago GG, Rodríguez-Frade JM, et al. (January 2003)."CCR7-mediated physiological lymphocyte homing involves activation of a tyrosine kinase pathway".Blood.101(1): 38–44.doi:10.1182/blood-2002-03-0841.PMID12393730.
• Wolf M, Clark-Lewis I, Buri C, Langen H, Lis M, Mazzucchelli L (April 2003)."Cathepsin D specifically cleaves the chemokines macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta, and SLC that are expressed in human breast cancer".The American Journal of Pathology.162(4): 1183–1190.doi:10.1016/S0002-9440(10)63914-4.PMC1851240.PMID12651610.
• Weninger W, Carlsen HS, Goodarzi M, Moazed F, Crowley MA, Baekkevold ES, et al. (May 2003)."Naive T cell recruitment to nonlymphoid tissues: a role for endothelium-expressed CC chemokine ligand 21 in autoimmune disease and lymphoid neogenesis".Journal of Immunology.170(9): 4638–4648.doi:10.4049/jimmunol.170.9.4638.PMID12707342.
• Nagakubo D, Murai T, Tanaka T, Usui T, Matsumoto M, Sekiguchi K, Miyasaka M (July 2003)."A high endothelial venule secretory protein, mac25/angiomodulin, interacts with multiple high endothelial venule-associated molecules including chemokines".Journal of Immunology.171(2): 553–561.doi:10.4049/jimmunol.171.2.553.PMID12847218.