CCL21

Last updated
CCL21
Available structures
PDB Ortholog search: PDBe RCSB
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
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
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
PubMed search [3] [4]
Wikidata
View/Edit Human View/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]

Contents

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]

Related Research Articles

<span class="mw-page-title-main">Dendritic cell</span> Accessory cell of the mammalian immune system

A dendritic cell (DC) is an antigen-presenting cell of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system. They act as messengers between the innate and adaptive immune systems.

<span class="mw-page-title-main">Chemokine</span> Small cytokines or signaling proteins secreted by cells

Chemokines, or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addition to playing a major role in the activation of host immune responses, chemokines are important for biological processes, including morphogenesis and wound healing, as well as in the pathogenesis of diseases like cancers.

<span class="mw-page-title-main">Memory B cell</span> Cell of the adaptive immune system

In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quiescent state, sometimes for decades. Their function is to memorize the characteristics of the antigen that activated their parent B cell during initial infection such that if the memory B cell later encounters the same antigen, it triggers an accelerated and robust secondary immune response. Memory B cells have B cell receptors (BCRs) on their cell membrane, identical to the one on their parent cell, that allow them to recognize antigen and mount a specific antibody response.

<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 that are now officially named CCL3 and CCL4, respectively. However, other names can sometimes be encountered, especially in older literature, 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">Follicular dendritic cells</span> Immune cells found in lymph nodes

Follicular dendritic cells (FDC) are cells of the immune system found in primary and secondary lymph follicles of the B cell areas of the lymphoid tissue. Unlike dendritic cells (DC), FDCs are not derived from the bone-marrow hematopoietic stem cell, but are of mesenchymal origin. Possible functions of FDC include: organizing lymphoid tissue's cells and microarchitecture, capturing antigen to support B cell, promoting debris removal from germinal centers, and protecting against autoimmunity. Disease processes that FDC may contribute include primary FDC-tumor, chronic inflammatory conditions, HIV-1 infection development, and neuroinvasive scrapie.

High endothelial venules (HEV) are specialized post-capillary venules characterized by plump endothelial cells as opposed to the usual flatter endothelial cells found in regular venules. HEVs enable lymphocytes circulating in the blood to directly enter a lymph node.

<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">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.

Chemokine ligand 17 (CXCL17) is a small cytokine belonging to the CXC chemokine family that has been identified in humans and mice. CXCL17 attracts dendritic cells and monocytes and is regulated in tumors. It is also known as VEGF co-regulated chemokine 1 (VCC-1) and dendritic cell- and monocyte-attracting chemokine-like protein (DMC). This chemokine is constitutively expressed in the lung. The gene for human CXCL17 is located on chromosome 19.

<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.

Lymphocyte homing receptors are cell adhesion molecules expressed on lymphocyte cell membranes that recognize addressins on target tissues. Lymphocyte homing refers to adhesion of the circulating lymphocytes in blood to specialized endothelial cells within lymphoid organs. These diverse tissue-specific adhesion molecules on lymphocytes and on endothelial cells contribute to the development of specialized immune responses.

<span class="mw-page-title-main">C-C chemokine receptor type 7</span> Protein-coding gene in the species Homo sapiens

C-C chemokine receptor type 7 is a protein that in humans is encoded by the CCR7 gene. Two ligands have been identified for this receptor: the chemokines ligand 19 (CCL19/ELC) and ligand 21 (CCL21). 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. 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 by detecting specific chemokines, which these tissues secrete.

<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">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">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.

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

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Further reading