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CCL21

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CCL21
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCCL21, 6Ckine, CKb9, ECL, SCYA21, SLC, TCA4, C-C motif chemokine ligand 21
External IDsOMIM: 602737; MGI: 1349183; HomoloGene: 2247; GeneCards: CCL21; OMA:CCL21 - orthologs
Orthologs
SpeciesHumanMouse
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 MbChr 4: 42.77 – 42.77 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Chemokine (C-C motif) ligand 21 (CCL21) is a small cytokine belonging to the CC chemokine family. This chemokine is also known as 6Ckine (because it has six conserved cysteine residues instead of the four cysteines typical to chemokines), exodus-2, and secondary lymphoid-tissue chemokine (SLC).[5][6][7] CCL21 elicits its effects by binding to a cell surface chemokine receptor known as CCR7.[8] The main function of CCL21 is to guide CCR7 expressing leukocytes to the secondary lymphoid organs, such as lymph nodes and Peyer´s patches.[9]

Gene

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The gene for CCL21 is located on human chromosome 9.[10] CCL21 is classified as a homeostatic chemokine, it is produced constitutively. However, its expression increases during inflammation.[9][11]

Protein structure

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Chemokine CCL21 contains an extended C-terminus which is not found in CCL19, another ligand of CCR7. C-terminal tail is composed of 37 amino acids rich in positively charged residues and therefore, it has high affinity for negatively charged molecules of the extracellular matrix. The cleavage of the C-terminal tail by peptidases produces a soluble form of CCL21.[12] The soluble CCL21 occurs also in physiological conditions. It does not bind to extracellular matrix and therefore, its function differs from the function of the full-length CCL21.[11]

Function

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Migration to secondary lymphoid organs

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Naïve T cells circulate through secondary lymphoid organs until they encounter the antigen.[13] CCL21 is a chemokine involved in the recruitment of T cells into secondary lymphoid organs. It is produced by lymphatic endothelial cells and lymph node stromal cells.[7][12] Full-length CCL21 is bound to glycosaminoglycans, and endothelial cells and it induces the chemotactic migration of T cells and the cell adhesion caused by integrin activation.[9] In contrast, the soluble CCL21 is not involved in the induction of the cell adhesion.[11] After T cells enter the lymph nodes through high endothelial venules, they are attracted to the T cell zone, where fibroblastic reticular cells are the abundant source of CCL21.[13][9]

CCL21/CCR7 interaction also plays a role in the migration of dendritic cells to the secondary lymphoid organs.[14][11][9] Dendritic cells upregulate the expression of CCR7 during their maturation.[14] CCL21 is bound to the lymphatic vessels and attracts CCR7 expressing dendritic cells from peripheral tissues. Then they migrate along the chemokine gradient to the lymph node where they present the antigen to T cells.[9] Interactions between dendritic cells and T cells are necessary for the initiation of the adaptive immune response.[15] When CCL21 is not recognized by the cells (for example in CCR7-deficient mice), a delayed and reduced adaptive immune response occurs due to reduced interactions between dendritic cells and T cells in the lymph nodes.[9] Semi-mature dendritic cells express CCR7 in the absence of a danger signal. They use CCL21 chemokine gradient for the migration to the lymph nodes even when there is no inflammation in the body, and they contribute to peripheral tolerance.[11]

Other cells using chemokine CCL21 for the migration to the lymph nodes are B cells. However, they are less dependent on it in comparison to T cells.[9]

T cell development in the thymus

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CCL21/CCR7 interaction plays a role in the T cell development in the thymus. CCL21 is produced in the thymus medulla by medullary thymic epithelial cells, and it attracts single positive thymocytes from the thymus cortex to the medulla, where they undergo negative selection to delete autoreactive thymocytes.[9]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000137077 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000094686 – 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. ^ 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. PMID 9257816. S2CID 23429282.
  6. ^ 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. PMID 9300671. S2CID 33971251.
  7. ^ a b 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. PMID 9235955.
  8. ^ 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. PMID 9507024.
  9. ^ a b c d e f g h i Comerford I, Harata-Lee Y, Bunting MD, Gregor C, Kara EE, McColl SR (June 2013). "A myriad of functions and complex regulation of the CCR7/CCL19/CCL21 chemokine axis in the adaptive immune system". Cytokine & Growth Factor Reviews. 24 (3): 269–283. doi:10.1016/j.cytogfr.2013.03.001. PMID 23587803.
  10. ^ Blanchet X, Langer M, Weber C, Koenen RR, von Hundelshausen P (July 2012). "Touch of chemokines". Frontiers in Immunology. 3: 175. doi:10.3389/fimmu.2012.00175. PMC 3394994. PMID 22807925.
  11. ^ a b c d e Hauser MA, Legler DF (June 2016). "Common and biased signaling pathways of the chemokine receptor CCR7 elicited by its ligands CCL19 and CCL21 in leukocytes". Journal of Leukocyte Biology. 99 (6): 869–882. doi:10.1189/jlb.2MR0815-380R. PMID 26729814. S2CID 5005741.
  12. ^ a b Jørgensen AS, Rosenkilde MM, Hjortø GM (March 2018). "Biased signaling of G protein-coupled receptors - From a chemokine receptor CCR7 perspective". General and Comparative Endocrinology. 258: 4–14. doi:10.1016/j.ygcen.2017.07.004. PMID 28694053.
  13. ^ a b Hunter MC, Teijeira A, Halin C (December 2016). "T Cell Trafficking through Lymphatic Vessels". Frontiers in Immunology. 7: 613. doi:10.3389/fimmu.2016.00613. PMC 5174098. PMID 28066423.
  14. ^ a b Förster R, Davalos-Misslitz AC, Rot A (May 2008). "CCR7 and its ligands: balancing immunity and tolerance". Nature Reviews. Immunology. 8 (5): 362–371. doi:10.1038/nri2297. PMID 18379575. S2CID 19725359.
  15. ^ Bousso P (September 2008). "T-cell activation by dendritic cells in the lymph node: lessons from the movies". Nature Reviews. Immunology. 8 (9): 675–684. doi:10.1038/nri2379. PMID 19172690. S2CID 6551798.
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Further reading

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