Alternative titles; symbols
HGNC Approved Gene Symbol: CCL19
Cytogenetic location: 9p13.3 Genomic coordinates (GRCh38): 9:34,689,570-34,691,276 (from NCBI)
Yoshida et al. (1997) and Rossi et al. (1997) cloned a novel chemokine receptor of the CC type; they named it 'EBI1 ligand chemokine' (ELC) and 'macrophage inflammatory protein-3-beta' (MIP-3-beta), respectively.
Yoshida et al. (1997) identified a sequence with homology to CC chemokines in the EST database. They used PCR to clone the corresponding cDNA from a human fetal lung cDNA library. The gene encoded a 98-amino polypeptide with a 21-amino acid putative signal sequence. Northern blot analysis revealed that the gene was expressed at high levels in thymus and lymph nodes, at intermediate levels in colon and trachea, and at low levels in spleen, small intestine, lung, kidney, and stomach. Yoshida et al. (1997) expressed the ELC gene in 293/EBNA-1 cells and observed an expressed protein of the predicted size (12 kD) that bound specifically to EBI1 (600242). Cells expressing EBI1 had chemotactic responses to ELC protein.
Rossi et al. (1997) used PCR of human-rodent hybrids to map the SCYA19 gene to human chromosome 9. Yoshida et al. (1997) used somatic hybrid and radiation hybrid analyses to map SCYA19 to human chromosome 9p13. They noted that the SCYA19 gene is not part of the CC chemokine gene cluster on chromosome 17.
Robbiani et al. (2000) showed that migration of dendritic cells (DCs) from skin to lymph nodes utilizes the leukotriene C4 (LTC4; see 246530) transporter MRP1 (158343). DC mobilization from the epidermis and trafficking into lymphatic vessels was greatly reduced in Mrp1 -/- mice, but migration was restored by exogenous cysteinyl leukotrienes LTC4 or LTD4. In vitro, these cysteinyl leukotrienes promoted optimal chemotaxis to the chemokine CCL19 but not to other related chemokines. Antagonism of CCL19 in vivo prevented DC migration out of the epidermis. Thus, the authors concluded that MRP1 regulates DC migration to lymph nodes, apparently by transporting LTC4, which in turn promotes chemotaxis to CCL19 and mobilization of DCs from the epidermis.
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 (also known as EBI1), the receptor for the T-zone chemokines CCL19 and CCL21 (602737), 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.
CXCL13, CCL21, and CCL19 are constitutively expressed in secondary lymphoid organs and are inducibly expressed in lung after influenza infection. 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 induced bronchus-associated lymphoid tissue 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.
Using animal modeling and gene expression profiling, Buonamici et al. (2009) showed that the chemokine receptor CCR7 (600242) is the essential adhesion signal required for the targeting of leukemic T cells into the central nervous system (CNS) in T-ALL. Ccr7 gene expression is controlled by the activity of the T-ALL oncogene Notch1 (190198) and is expressed in human tumors carrying Notch1-activating mutations. Silencing of either CCR7 or its chemokine ligand CCL19 in an animal model of T-ALL specifically inhibited CNS infiltration. Furthermore, murine CNS targeting by human T-ALL cells depended on their ability to express CCR7. Buonamici et al. (2009) concluded that their studies identified a single chemokine-receptor interaction as a CNS 'entry' signal, and opened the way for future pharmacologic targeting. Targeted inhibition of CNS involvement in T-ALL could potentially decrease the intensity of CNS-targeted therapy, thus reducing its associated short- and long-term complications.
By screening for proteins that could bind human CCRL2 (608379), Leick et al. (2009) identified CCL19 as a CCRL2 ligand. CCL19 bound to CCRL2-expressing cells with an affinity comparable to its binding of CCR7, but binding to CCRL2 did not result in cellular activation for calcium mobilization or migration. Confocal microscopy showed that CCRL2 was constitutively recycled via clathrin-coated pits and could internalize CCL19, as well as anti-CCRL2 antibodies. Leick et al. (2009) concluded that CCRL2 is a nonclassical chemokine receptor that may be involved in modulating CCL19-mediated lymphocyte and dendritic cell trafficking.
Buonamici, S., Trimarchi, T., Ruocco, M. G., Reavie, L., Cathelin, S., Mar, B. G., Klinakis, A., Lukyanov, Y., Tseng, J.-C., Sen, F., Gehrie, E., Li, M., and 10 others. CCR7 signalling as an essential regulator of CNS infiltration in T-cell leukaemia. Nature 459: 1000-1004, 2009. [PubMed: 19536265] [Full Text: https://doi.org/10.1038/nature08020]
Leick, M., Catusse, J., Follo, M., Nibbs, R. J., Hartmann, T. N., Veelken, H., Burger, M. CCL19 is a specific ligand of the constitutively recycling atypical human chemokine receptor CRAM-B. Immunology 129: 536-546, 2009. [PubMed: 20002784] [Full Text: https://doi.org/10.1111/j.1365-2567.2009.03209.x]
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]
Robbiani, D. F., Finch, R. A., Jager, D., Muller, W. A., Sartorelli, A. C., Randolph, G. J. The leukotriene C4 transporter MRP1 regulates CCL19 (MIP-3-beta, ELC)-dependent mobilization of dendritic cells to lymph nodes. Cell 103: 757-768, 2000. [PubMed: 11114332] [Full Text: https://doi.org/10.1016/s0092-8674(00)00179-3]
Rossi, D. L., Vicari, A. P., Franz-Bacon, K., McClanahan, T. K., Zlotnik, A. Identification through bioinformatics of two new macrophage proinflammatory human chemokines. J. Immun. 158: 1033-1036, 1997. Note: Erratum: J. Immun. 163: 1091 only, 1999. [PubMed: 9013939]
Yoshida, R., Imai, T., Hieshima, K., Kusuda, J., Baba, M., Kitaura, M., Nishimura, M., Kakizaki, M., Nomiyama, H., Yoshie, O. Molecular cloning of a novel human CC chemokine EBI1-ligand chemokine that is a specific ligand for EBI1, CCR7. J. Biol. Chem. 272: 13803-13809, 1997. [PubMed: 9153236] [Full Text: https://doi.org/10.1074/jbc.272.21.13803]