Alternative titles; symbols
HGNC Approved Gene Symbol: CCL21
Cytogenetic location: 9p13.3 Genomic coordinates (GRCh38): 9:34,709,005-34,710,136 (from NCBI)
CCL21 is a ligand for CCR7 (600242) and guides the interactions between CCR7+ T cells and antigen-presenting cells (APCs) needed for T cell education and priming. These events are involved both in triggering adaptive immunity and maintaining peripheral tolerance (summary by Shields et al., 2010).
Chemokines are a family of proteins that direct leukocyte migration and activation to inflammatory stimuli. In the C-C, or beta, subfamily, the first 2 conserved cysteines are adjacent to each other (see SCYA20; 601960). Hedrick and Zlotnik (1997), Hromas et al. (1997), and Nagira et al. (1997) identified human ESTs encoding the C-C chemokine SCYA21, which they designated 6CKINE, EXODUS2, and secondary lymphoid tissue chemokine (SLC), respectively. By Northern blot analysis, Hromas et al. (1997) showed that the 0.9-kb SCYA21 mRNA is expressed preferentially in lymph node tissue. Nagira et al. (1997) reported that the predicted 134-amino acid SCYA21 protein has a 23-amino acid signal sequence and a unique, approximately 30-amino acid C-terminal extension which contains 2 extra cysteines. Unlike other C-C chemokines, SCYA21 was specifically chemotactic for lymphocytes. Hedrick and Zlotnik (1997) cloned a mouse Scya21 cDNA and reported that the predicted amino acid sequences of mouse and human SCYA21 are 86% similar.
B lymphocytes recirculate between B cell-rich compartments (follicles or B zones) in secondary lymphoid organs, surveying for antigen. After antigen binding, B cells move to the boundary of B and T zones to interact with T-helper cells. Reif et al. (2002) demonstrated that antigen-engaged B cells have increased expression of CCR7 (600242), the receptor for the T-zone chemokines CCL19 (also known as SCYA19) and CCL21, and that they exhibit increased responsiveness to both chemoattractants. In mice lacking lymphoid CCL19 and CCL21 chemokines, or with B cells that lack CCR7, antigen engagement fails to cause movement to the T zone. Using retroviral-mediated gene transfer, the authors demonstrated that increased expression of CCR7 is sufficient to direct B cells to the T zone. Reciprocally, overexpression of CXCR5 (601613), the receptor for the B-zone chemokine CXCL13 (605149), is sufficient to overcome antigen-induced B-cell movement to the T zone. Reif et al. (2002) concluded that their findings defined the mechanism of B-cell relocalization in response to antigen, and established that cell position in vivo can be determined by the balance of responsiveness to chemoattractants made in separate but adjacent zones.
Although chemokine signaling is often promiscuous, signaling events between members of the distinct chemokine classes (CXC, CC, CX3C, and C) are almost never observed. Dijkstra et al. (2004) showed that human CCL21, in the absence of its primary receptor, CCR7, is a functional ligand for CXCR3 (300574), inducing chemotaxis in adult microglial cells, but not in kidney epithelial cells. CCL21-induced chemotaxis could be inhibited by the CXCR3 ligand, CXCL10 (147310), whereas CXCL10 had no effect on CX3CL1 (601880) chemotactic activity. Fluorescence microscopy demonstrated that CXCR3 was expressed predominantly in microglial cytoplasm. Dijkstra et al. (2004) concluded that CCL21 signaling through CXCR3 depends on the cellular background in which CXCR3 is expressed.
Moyron-Quiroz et al. (2004) showed that mice lacking spleen, lymph nodes, and Peyer patches generated robust B- and T-cell responses to influenza at sites of induced bronchus-associated lymphoid tissue (iBALT). Cxcl13 and Ccl21 were expressed at sites of iBALT formation. These mice cleared influenza infection and survived higher challenge doses than did normal mice. Moyron-Quiroz et al. (2004) proposed that the immune responses of these mice are not only more protective, but also less pathologic, than systemic immune responses.
Rangel-Moreno et al. (2007) found that, in the absence of spleen and lymph nodes, pulmonary expression of the Ccr7 ligands Ccl19 and Ccl21 was critical for local immune responses to influenza virus infection in mice. The Ccr7 ligands and Cxcl13 were essential for iBALT formation. Fluorescence microscopy demonstrated expression of these homeostatic chemokines in nonhematopoietic cells in high endothelial venules in lungs of influenza-infected mice. Rangel-Moreno et al. (2007) concluded that CCL19, CCL21, and CXCL13 are expressed at sites of inflammation and contribute to development of local lymphoid tissue, as well as to initiation and expansion of adaptive immune responses.
Mueller et al. (2007) showed that CCL21 and CXCL13 are transiently downregulated within lymphoid tissues during immune responses by a mechanism controlled by the cytokine interferon-gamma (147570). This modulation altered the localization of lymphocytes and dendritic cells within responding lymphoid tissues. As a consequence, priming of T cell responses to a second distinct pathogen after chemokine modulation became impaired. Mueller et al. (2007) proposed that this transient chemokine modulation may help orchestrate local cellularity, thus minimizing competition for space and resources in activated lymphoid tissues.
In mice, Shields et al. (2010) found that Ccl21 expression by melanoma tumors was associated with an immunotolerant microenvironment, which included the induction of lymphoid-like reticular stromal networks, an altered cytokine milieu, and the recruitment of regulatory leukocyte populations. In contrast, Ccl21-deficient tumors induced antigen-specific immunity. Ccl21-mediated immune tolerance was dependent on host rather than tumor expression of the Ccl21 receptor Ccr7 (600242), and could protect distant, coimplanted Ccl21-deficient tumors and even nonsyngeneic allografts from rejection. Shields et al. (2010) concluded that by altering the tumor microenvironment, Ccl21-secreting tumors shift the host immune response from immunogenic to tolerogenic, which facilitates tumor progression.
Using global expression analysis, Harhausen et al. (2010) showed that Cd93 (120577) mRNA was highly induced in endothelial cells, selected macrophages, and microglia of mice after transient focal cerebral ischemia. Occlusion of the middle cerebral artery followed by reperfusion in Cd93 -/- mice resulted in increased leukocyte infiltration into brain. Infarct volumes were greater in Cd93 -/- mice than wildtype mice after short occlusion and long reperfusion times, but not after long occlusion and short reperfusion times. Transcription profiles of Cd93 -/- mice and wildtype mice, with confirmation by PCR and immunohistochemistry, detected significant upregulation of Ccl21 in untreated and treated Cd93 -/- mice at all time points. Harhausen et al. (2010) concluded that CCL21 contributes to neurodegeneration and that the neuroprotective effect of CD93 is mediated via suppression of the neuroinflammatory response through downregulation of CCL21.
Weber et al. (2013) identified endogenous gradients of the chemokine CCL21 within mouse skin and showed that they guide dendritic cells toward lymphatic vessels. Quantitative imaging revealed depots of CCL21 within lymphatic endothelial cells and steeply decaying gradients within the perilymphatic interstitium. These gradients matched the migratory patterns of the dendritic cells, which directionally approach vessels from a distance of up to 90 microns. Interstitial CCL21 is immobilized to heparan sulfates, and its experimental delocalization or swamping the endogenous gradients abolished directed migration. Weber et al. (2013) concluded that their findings functionally established the concept of haptotaxis, directed migration along immobilized gradients, in tissues.
The addition of polysialic acid to N- and/or O-linked glycans, referred to as polysialylation, is a rare posttranslational modification that is mainly known to control the developmental plasticity of the nervous system. Kiermaier et al. (2016) demonstrated that CCR7, the central chemokine receptor controlling immune cell trafficking to secondary lymphatic organs, carries polysialic acid. This modification is essential for the recognition of the CCR7 ligand CCL21. As a consequence, dendritic cell trafficking was abrogated in polysialyltransferase-deficient mice, manifesting as disturbed lymph node homeostasis and unresponsiveness to inflammatory stimuli. Structure-function analysis of chemokine-receptor interactions revealed that CCL21 adopts an autoinhibited conformation, which is released upon interaction with polysialic acid. Thus, Kiermaier et al. (2016) concluded that they described a glycosylation-mediated immune cell trafficking disorder and its mechanistic basis.
Zhao et al. (2020) found that antigen-activated male B cells did not position themselves as efficiently as female B cells in the center of follicles in secondary lymphoid organs, in which germinal center normally develop. Moreover, GPR174 (300903), an X-chromosome-encoded G protein-coupled receptor, suppressed the formation of germinal centers in male, but not female, mice. This effect was intrinsic to B cells, and correlated with the GPR174-enhanced positioning of B cells towards the T-cell-B-cell border of follicles, and the distraction of male, but not female, B cells from S1PR2-driven follicle-center localization. Biochemical fractionation of conditioned media that induced B-cell migration in a GPR174-dependent manner identified CCL21 as a GPR174 ligand. In response to CCL21, GPR174 triggered a calcium flux and preferentially induced the migration of male B cells; GPR174 also became associated with more G-alpha-i (see 139310) protein in male than in female B cells. Male B cells from orchidectomized mice exhibited impaired GPR174-mediated migration to CCL21, and testosterone treatment rescued this defect. Female B cells from testosterone-treated mice exhibited male-like GPR174-G-alpha-i association and GPR174-mediated migration. Deleting GPR174 from male B cells caused more efficient positioning towards the follicular center, the formation of more germinal centers, and an increased susceptibility to B-cell-dependent experimental autoimmune encephalomyelitis. Zhao et al. (2020) concluded that by identifying GPR174 as a receptor for CCL21 and demonstrating its sex-dependent control of B-cell positioning and participation in germinal centers, they revealed a mechanism by which B cell physiology is fine-tuned to impart sexual dimorphism to humoral immunity.
By somatic cell hybrid and radiation hybrid analyses, Nagira et al. (1997) mapped the SCYA21 gene to 9p13. Using a YAC contig and BAC clones from this region, they found that the SCYA21 and SCYA19 (602227) genes are located within 120 kb of each other.
Using transgenic mice, adoptive transfer, and flow cytometric analysis, Ploix et al. (2001) showed that expression of a CCR7 ligand, CCL21, is necessary for CD4+ but not CD8+ T cells to reach their steady state 'set point,' even in lymphopenic recipients. In addition, adoptive transfer of antigen-specific T cells into nonlymphopenic mice overexpressing CCL21 caused autoimmune diabetes. The authors proposed that perturbations in the expression of CCR7 ligands, such as CCL21 or CCL19, may alter susceptibility to autoimmunity.
Using global expression analysis, Harhausen et al. (2010) showed that Cd93 (120577) mRNA was highly induced in endothelial cells, selected macrophages, and microglia of mice after transient focal cerebral ischemia. Occlusion of the middle cerebral artery followed by reperfusion in Cd93 -/- mice resulted in increased leukocyte infiltration into brain. Infarct volumes were greater in Cd93 -/- mice than wildtype mice after short occlusion and long reperfusion times, but not after long occlusion and short reperfusion times. Transcription profiles of Cd93 -/- mice and wildtype mice, with confirmation by PCR and immunohistochemistry, detected significant upregulation of Ccl21 in untreated and treated Cd93 -/- mice at all time points. Harhausen et al. (2010) concluded that CCL21 contributes to neurodegeneration and that the neuroprotective effect of CD93 is mediated via suppression of the neuroinflammatory response through downregulation of CCL21.
Dijkstra, I. M., Hulshof, S., van der Valk, P., Boddeke, H. W. G. M., Biber, K. Cutting edge: activity of human adult microglia in response to CC chemokine ligand 21. J. Immun. 172: 2744-2747, 2004. [PubMed: 14978072] [Full Text: https://doi.org/10.4049/jimmunol.172.5.2744]
Harhausen, D., Prinz, V., Ziegler, G., Gertz, K., Endres, M., Lehrach, H., Gasque, P., Botto, M., Stahel, P. F., Dirnagl, U., Nietfeld, W., Trendelenburg, G. CD93/AA4.1: a novel regulator of inflammation in murine focal cerebral ischemia. J. Immun. 184: 6407-6417, 2010. [PubMed: 20439917] [Full Text: https://doi.org/10.4049/jimmunol.0902342]
Hedrick, J. A., Zlotnik, A. Identification and characterization of a novel beta chemokine containing six conserved cysteines. J. Immun. 159: 1589-1593, 1997. [PubMed: 9257816]
Hromas, R., Kim, C. H., Klemsz, M., Krathwohl, M., Fife, K., Cooper, S., Schnizlein-Bick, C., Broxmeyer, H. E. Isolation and characterization of Exodus-2, a novel C-C chemokine with a unique 37-amino acid carboxyl-terminal extension. J. Immun. 159: 2554-2558, 1997. [PubMed: 9300671]
Kiermaier, E., Moussion, C., Veldkamp, C. T., Gerardy-Schahn, R., de Vries, I., Williams, L. G., Chaffee, G. R., Phillips, A. J., Freiberger, F., Imre, R., Taleski, D., Payne, R. J., Braun, A., Forster, R., Mechtler, K., Muhlenhoff, M., Volkman, B. F., Sixt, M. Polysialylation controls dendritic cell trafficking by regulating chemokine recognition. Science 351: 186-190, 2016. [PubMed: 26657283] [Full Text: https://doi.org/10.1126/science.aad0512]
Moyron-Quiroz, J. E., Rangel-Moreno, J., Kusser, K., Hartson, L., Sprague, F., Goodrich, S., Woodland, D. L., Lund, F. E., Randall, T. D. Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nature Med. 10: 927-934, 2004. [PubMed: 15311275] [Full Text: https://doi.org/10.1038/nm1091]
Mueller, S. N., Hosiawa-Meagher, K. A., Konieczny, B. T., Sullivan, B. M., Bachmann, M. F., Locksley, R. M., Ahmed, R., Matloubian, M. Regulation of homeostatic chemokine expression and cell trafficking during immune responses. Science 317: 670-674, 2007. [PubMed: 17673664] [Full Text: https://doi.org/10.1126/science.1144830]
Nagira, M., Imai, T., Hieshima, K., Kusuda, J., Ridanpaa, M., Takagi, S., Nishimura, M., Kakizaki, M., Nomiyama, H., Yoshie, O. Molecular cloning of a novel human CC chemokine secondary lymphoid-tissue chemokine that is a potent chemoattractant for lymphocytes and mapped to chromosome 9p13. J. Biol. Chem. 272: 19518-19524, 1997. [PubMed: 9235955] [Full Text: https://doi.org/10.1074/jbc.272.31.19518]
Ploix, C., Lo, D., Carson, M. J. A ligand for the chemokine receptor CCR7 can influence the homeostatic proliferation of CD4 T cells and progression of autoimmunity. J. Immun. 167: 6724-6730, 2001. [PubMed: 11739486] [Full Text: https://doi.org/10.4049/jimmunol.167.12.6724]
Rangel-Moreno, J., Moyron-Quiroz, J. E., Hartson, L., Kusser, K., Randall, T. D. Pulmonary expression of CXC chemokine ligand 13, CC chemokine ligand 19, and CC chemokine ligand 21 is essential for local immunity to influenza. Proc. Nat. Acad. Sci. 104: 10577-10582, 2007. [PubMed: 17563386] [Full Text: https://doi.org/10.1073/pnas.0700591104]
Reif, K., Ekland, E. H., Ohl, L., Nakano, H., Lipp, M., Forster, R., Cyster, J. G. Balanced responsiveness to chemoattractants from adjacent zones determines B-cell position. Nature 416: 94-99, 2002. [PubMed: 11882900] [Full Text: https://doi.org/10.1038/416094a]
Shields, J. D., Kourtis, I. C., Tomei, A. A., Roberts, J. M., Swartz, M. A. Induction of lymphoidlike stroma and immune escape by tumors that express the chemokine CCL21. Science 328: 749-752, 2010. [PubMed: 20339029] [Full Text: https://doi.org/10.1126/science.1185837]
Weber, M., Hauschild, R., Schwarz, J., Moussion, C., de Vries, I., Legler, D. F., Luther, S. A., Bollenbach, T., Sixt, M. Interstitial dendritic cell guidance by haptotactic chemokine gradients. Science 339: 328-332, 2013. [PubMed: 23329049] [Full Text: https://doi.org/10.1126/science.1228456]
Zhao, R., Chen, X., Ma, W., Zhang, J., Guo, J., Zhong, X., Yao, J., Sun, J., Rubinfien, J., Zhou, X., Wang, J., Qi, H. A GPR174-CCL21 module imparts sexual dimorphism to humoral immunity. Nature 577: 416-420, 2020. [PubMed: 31875850] [Full Text: https://doi.org/10.1038/s41586-019-1873-0]