Mammalian protein found in Homo sapiens
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
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
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
Migration to secondary lymphoid organs
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
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
^
a
b
c
GRCh38: Ensembl release 89: ENSG00000137077 –
Ensembl , May 2017
^
a
b
c
GRCm38: Ensembl release 89: ENSMUSG00000094686 –
Ensembl , May 2017
^
"Human PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .
^
"Mouse PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .
^ 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 .
^ 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 .
^
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 .
^ 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 .
^
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 .
^ 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 .
^
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 .
^
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 .
^
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 .
^
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 .
^ 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 .
External links
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 .
PMID
9235955 .
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 .
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 .
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 .
PMC
18193 .
PMID
9419363 .
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 .
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 .
PMC
2132769 .
PMID
9585422 .
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 .
PMID
10201891 .
S2CID
23946439 .
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 .
PMID
10706668 .
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 .
PMID
10861057 .
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 .
PMID
11083865 .
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 .
PMID
11929789 .
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 .
PMC
1867219 .
PMID
11943728 .
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 .
PMID
11970971 .
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 .
PMID
12393410 .
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 .
PMID
12393730 .
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 .
PMC
1851240 .
PMID
12651610 .
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 .
PMID
12707342 .
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 .
PMID
12847218 .
By family
By function/ cell