CCL21 explained

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).^{[1] [2] [3]} CCL21 elicits its effects by binding to a cell surface chemokine receptor known as CCR7.^[4] The main function of CCL21 is to guide CCR7 expressing leukocytes to the secondary lymphoid organs, such as lymph nodes and Peyer´s patches.^[5]

Gene

The gene for CCL21 is located on human chromosome 9.^[6] CCL21 is classified as a homeostatic chemokine, it is produced constitutively. However, its expression increases during inflammation.^[7]

Protein structure

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.^[8] 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.

Function

Migration to secondary lymphoid organs

Naïve T cells circulate through secondary lymphoid organs until they encounter the antigen.^[9] 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. 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. In contrast, the soluble CCL21 is not involved in the induction of the cell adhesion. 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.

CCL21/CCR7 interaction also plays a role in the migration of dendritic cells to the secondary lymphoid organs.^[10] Dendritic cells upregulate the expression of CCR7 during their maturation. 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. Interactions between dendritic cells and T cells are necessary for the initiation of the adaptive immune response.^[11] 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. 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.

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.

T cell development in the thymus

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.

Further reading

• Nagira M, Imai T, Hieshima K, Kusuda J, Ridanpää M, Takagi S, Nishimura M, Kakizaki M, Nomiyama H, Yoshie O . 6 . 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 . August 1997 . 9235955 . 10.1074/jbc.272.31.19518 . free .
• Hedrick JA, Zlotnik A . Identification and characterization of a novel beta chemokine containing six conserved cysteines . Journal of Immunology . 159 . 4 . 1589–1593 . August 1997 . 10.4049/jimmunol.159.4.1589 . 9257816 . 23429282 . free .
• Hromas R, Kim CH, Klemsz M, Krathwohl M, Fife K, Cooper S, Schnizlein-Bick C, Broxmeyer HE . 6 . 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 . September 1997 . 10.4049/jimmunol.159.6.2554 . 9300671 . 33971251 . free .
• Gunn MD, Tangemann K, Tam C, Cyster JG, Rosen SD, Williams LT . 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 . January 1998 . 9419363 . 18193 . 10.1073/pnas.95.1.258 . free . 1998PNAS...95..258G .
• Yoshida R, Nagira M, Kitaura M, Imagawa N, Imai T, Yoshie O . Secondary lymphoid-tissue chemokine is a functional ligand for the CC chemokine receptor CCR7 . The Journal of Biological Chemistry . 273 . 12 . 7118–7122 . March 1998 . 9507024 . 10.1074/jbc.273.12.7118 . free .
• Campbell JJ, Bowman EP, Murphy K, Youngman KR, Siani MA, Thompson DA, Wu L, Zlotnik A, Butcher EC . 6 . 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 . May 1998 . 9585422 . 2132769 . 10.1083/jcb.141.4.1053 .
• Jenh CH, Cox MA, Kaminski H, Zhang M, Byrnes H, Fine J, Lundell D, Chou CC, Narula SK, Zavodny PJ . 6 . 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 . April 1999 . 10.4049/jimmunol.162.7.3765 . 10201891 . 23946439 . free .
• Gosling J, Dairaghi DJ, Wang Y, Hanley M, Talbot D, Miao Z, Schall TJ . 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 . March 2000 . 10706668 . 10.4049/jimmunol.164.6.2851 . free .
• Annunziato F, Romagnani P, Cosmi L, Beltrame C, Steiner BH, Lazzeri E, Raport CJ, Galli G, Manetti R, Mavilia C, Vanini V, Chantry D, Maggi E, Romagnani S . 6 . 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 . July 2000 . 10861057 . 10.4049/jimmunol.165.1.238 . free .
• Hirose J, Kawashima H, Yoshie O, Tashiro K, Miyasaka M . Versican interacts with chemokines and modulates cellular responses . The Journal of Biological Chemistry . 276 . 7 . 5228–5234 . February 2001 . 11083865 . 10.1074/jbc.M007542200 . free .
• Till KJ, Lin K, Zuzel M, Cawley JC . The chemokine receptor CCR7 and alpha4 integrin are important for migration of chronic lymphocytic leukemia cells into lymph nodes . Blood . 99 . 8 . 2977–2984 . April 2002 . 11929789 . 10.1182/blood.V99.8.2977 . free .
• Grant AJ, Goddard S, Ahmed-Choudhury J, Reynolds G, Jackson DG, Briskin M, Wu L, Hübscher SG, Adams DH . 6 . 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 . April 2002 . 11943728 . 1867219 . 10.1016/S0002-9440(10)62570-9 .
• Banas B, Wörnle M, Berger T, Nelson PJ, Cohen CD, Kretzler M, Pfirstinger J, Mack M, Lipp M, Gröne HJ, Schlöndorff D . 6 . Roles of SLC/CCL21 and CCR7 in human kidney for mesangial proliferation, migration, apoptosis, and tissue homeostasis . Journal of Immunology . 168 . 9 . 4301–4307 . May 2002 . 11970971 . 10.4049/jimmunol.168.9.4301 . free .
• Christopherson KW, Hood AF, Travers JB, Ramsey H, Hromas RA . Endothelial induction of the T-cell chemokine CCL21 in T-cell autoimmune diseases . Blood . 101 . 3 . 801–806 . February 2003 . 12393410 . 10.1182/blood-2002-05-1586 . free .
• Stein JV, Soriano SF, M'rini C, Nombela-Arrieta C, de Buitrago GG, Rodríguez-Frade JM, Mellado M, Girard JP, Martínez-A C . 6 . CCR7-mediated physiological lymphocyte homing involves activation of a tyrosine kinase pathway . Blood . 101 . 1 . 38–44 . January 2003 . 12393730 . 10.1182/blood-2002-03-0841 . free .
• Wolf M, Clark-Lewis I, Buri C, Langen H, Lis M, Mazzucchelli L . 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 . April 2003 . 12651610 . 1851240 . 10.1016/S0002-9440(10)63914-4 .
• Weninger W, Carlsen HS, Goodarzi M, Moazed F, Crowley MA, Baekkevold ES, Cavanagh LL, von Andrian UH . 6 . 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 . May 2003 . 12707342 . 10.4049/jimmunol.170.9.4638 . free .
• Nagakubo D, Murai T, Tanaka T, Usui T, Matsumoto M, Sekiguchi K, Miyasaka M . 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 . July 2003 . 12847218 . 10.4049/jimmunol.171.2.553 . free .

Notes and References

1. Hedrick JA, Zlotnik A . Identification and characterization of a novel beta chemokine containing six conserved cysteines . Journal of Immunology . 159 . 4 . 1589–1593 . August 1997 . 10.4049/jimmunol.159.4.1589 . 9257816 . 23429282 . free .
2. Hromas R, Kim CH, Klemsz M, Krathwohl M, Fife K, Cooper S, Schnizlein-Bick C, Broxmeyer HE . 6 . 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 . September 1997 . 10.4049/jimmunol.159.6.2554 . 9300671 . 33971251 . free .
3. Nagira M, Imai T, Hieshima K, Kusuda J, Ridanpää M, Takagi S, Nishimura M, Kakizaki M, Nomiyama H, Yoshie O . 6 . 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 . August 1997 . 9235955 . 10.1074/jbc.272.31.19518 . free .
4. Yoshida R, Nagira M, Kitaura M, Imagawa N, Imai T, Yoshie O . Secondary lymphoid-tissue chemokine is a functional ligand for the CC chemokine receptor CCR7 . The Journal of Biological Chemistry . 273 . 12 . 7118–7122 . March 1998 . 9507024 . 10.1074/jbc.273.12.7118 . free .
5. Comerford I, Harata-Lee Y, Bunting MD, Gregor C, Kara EE, McColl SR . 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 . June 2013 . 23587803 . 10.1016/j.cytogfr.2013.03.001 .
6. Blanchet X, Langer M, Weber C, Koenen RR, von Hundelshausen P . Touch of chemokines . Frontiers in Immunology . 3 . 175 . July 2012 . 22807925 . 3394994 . 10.3389/fimmu.2012.00175 . free .
7. Hauser MA, Legler DF . 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 . June 2016 . 26729814 . 10.1189/jlb.2MR0815-380R . 5005741 . free .
8. Jørgensen AS, Rosenkilde MM, Hjortø GM . Biased signaling of G protein-coupled receptors - From a chemokine receptor CCR7 perspective . General and Comparative Endocrinology . 258 . 4–14 . March 2018 . 28694053 . 10.1016/j.ygcen.2017.07.004 .
9. Hunter MC, Teijeira A, Halin C . T Cell Trafficking through Lymphatic Vessels . Frontiers in Immunology . 7 . 613 . December 2016 . 28066423 . 5174098 . 10.3389/fimmu.2016.00613 . free .
10. Förster R, Davalos-Misslitz AC, Rot A . CCR7 and its ligands: balancing immunity and tolerance . Nature Reviews. Immunology . 8 . 5 . 362–371 . May 2008 . 18379575 . 10.1038/nri2297 . 19725359 .
11. Bousso P . T-cell activation by dendritic cells in the lymph node: lessons from the movies . Nature Reviews. Immunology . 8 . 9 . 675–684 . September 2008 . 19172690 . 10.1038/nri2379 . 6551798 .