Disease relevance of Ccl19

• The antitumor efficacy of EBV-induced molecule 1 ligand CC chemokine (ELC/CCL19) was evaluated in a murine lung cancer model [1].
• They specifically chemotaxed towards both CCL19 or CCL21 in a concentration dependent and pertussis toxin-sensitive manner comparable to naive lymphocytes in vitro [2].
• This same AnTat 1.1 ELC, which is thus silent as the parasite develops in the insect vector, can be reactivated without duplication during the first parasitemia wave following cyclical transmission [3].
• To examine the potency of two beta-chemokines as immunomodulators, plasmid DNA encoding beta-chemokines CCL19 and CCL21 (CCR7L) was codelivered intranasally with plasmid DNA or recombinant vaccinia virus encoding herpes simplex virus (HSV) gB (HSV-gB) in a prime-and-boost vaccination strategy [4].
• In addition following mucosal challenge of herpes simplex virus-immune mice with virus, those that had received CCL21 or CCL19 during priming contained a higher frequency of responding CD4 T cells in lymph nodes and the site of infection [5].

High impact information on Ccl19

• We show that myosin containing the mutant ELC has abnormal function, map the mutant residues on the three-dimensional structure of myosin and suggest that the mutations disrupt the stretch activation response of the cardiac papillary muscles [6].
• CCL19 and CCL21 induce a potent proinflammatory differentiation program in licensed dendritic cells [7].
• Importantly, only activated DCs that migrated from the periphery to draining lymph nodes, but not resting steady-state DCs residing within lymph nodes, expressed high levels of CCR7 in vivo and responded to CCL19 with the production of proinflammatory cytokines [7].
• Subsequent studies showed that CCL19 enhanced T cell proliferation by inducing maturation of DCs, resulting in upregulation of costimulatory molecules and the production of proinflammatory cytokines [7].
• Thus, our data suggest an alternative G-alpha(i)-dependent, CCR7-CCL19/CCL21-independent mechanism for lymphocyte homing through HEVs which is strongly augmented in the presence of FTY720 [8].

Biological context of Ccl19

• Smaller amounts of ELC are made by DCs, predominantly of the CD8(+) phenotype [9].
• Plt mice, which lack expression of CCL19 and CCL21-ser, both ligands for CCR7 on HEVs, as well as CCR7-deficient mice, have a defective cell migration and reduced homing of lymphocytes [8].
• In the present study, we examined the effects of CCL19 and CCL21, 2 CCR7 ligands, on endocytosis of fluorescein isothiocyanate (FITC)-dextran by murine DCs [10].
• Gene duplications at the chemokine locus on mouse chromosome 4: multiple strain-specific haplotypes and the deletion of secondary lymphoid-organ chemokine and EBI-1 ligand chemokine genes in the plt mutation [11].
• Nonetheless, CCR7 expression and CCL19-driven chemotaxis remain intact [12].

Anatomical context of Ccl19

• Here we show that the homing of CXCR4-/- B cells is suppressed in CCL19 (ELC)- and CCL21 (SLC)-deficient paucity of lymph node T cells mice, but not in wild-type mice [13].
• The ability of ELC/CCL19 to chemoattract both dendritic cells and T lymphocytes formed the rationale for this study [1].
• Paucity of lymph node T-cells (plt/plt) mice lack CCL21-serine (ser) and CCL19 expression [14].
• We propose that ELC- and SLC-expressing T zone stromal cells play a central role in bringing naive T cells and DCs together for the initiation of immune responses [9].
• Using a combination of approaches, including bone marrow reconstitution and double in situ hybridization, we show in wild-type mice that ELC is expressed by T zone stromal cells that also make SLC [9].

Associations of Ccl19 with chemical compounds

• Compared with diluent-treated tumor-bearing mice, intratumoral injection of recombinant ELC/CCL19 led to significant systemic reduction in tumor volumes (p < 0.01) [1].
• Importantly, lungs from all groups expressed CXCL13, CCL21, and CCL19 and displayed organized follicular neolymphoid structures after infection with M. tuberculosis, which suggests that the lung served as a selectin ligand-independent priming site for immune responses to mycobacterial infection [15].
• Here, we report that Tyrphostin (Tyr) AG490, a pharmacological inhibitor of Janus family tyrosine kinases (Jaks), blocked the chemotactic response of primary mouse lymphocytes to CCL19 and CCL21 in a dose-dependent manner [16].
• The lymphocyte-expressed chemokine receptor CCR7 is playing an important role during this process, as its HEV-presented ligands CCL19 and CCL21 can trigger rapid integrin activation under flow in addition to inducing a chemotactic response, which may participate in transmigration and/or interstitial migration [16].

Regulatory relationships of Ccl19

• In addition, CCL19 rapidly enhanced Cdc42 and Rac activity in mature DCs [10].
• CCL19 significantly activated JNK in mature DCs at 15 min [17].

Other interactions of Ccl19

• LIGHT also upregulates CCL27, but not CCL19 and CCL21 expression in esDC [18].
• CXCL9 antagonism further extends prolonged cardiac allograft survival in CCL19/CCL21-deficient mice [14].
• ELC/CCL19 treated tumor-bearing mice showed enhanced frequency of tumor specific T lymphocytes secreting IFN-gamma [1].
• Differing activities of homeostatic chemokines CCL19, CCL21, and CXCL12 in lymphocyte and dendritic cell recruitment and lymphoid neogenesis [19].
• Spred1 overexpression also inhibited migration of cells in vitro in response to chemokines, CCL19 and CCL21 [20].

Analytical, diagnostic and therapeutic context of Ccl19

• These findings provide a strong rationale for further evaluation of ELC/CCL19 in tumor immunity and its use in cancer immunotherapy [1].
• On the other hand, CCL21 failed to induce rapid dendritic extension, even though a modest dendritic extension of mature DCs, compared to that by CCL19, was induced 8 or 24 hours after treatment with CCL21 [21].
• Binding assays on frozen sections of EAE brains demonstrated a functional involvement of CCL19 and CCL21 in adhesion strengthening of encephalitogenic T lymphocytes to inflamed venules in the brain [2].
• Taken together our data suggest that the lymphoid chemokines CCL19 and CCL21 besides regulating lymphocyte homing to secondary lymphoid tissue are involved in T lymphocyte migration into the immunoprivileged central nervous system during immunosurveillance and chronic inflammation [2].
• Stable overexpression of CCL19-IgG2b in BALB/c-derived J558L tumour cells fails to support tumour cell rejection following transplantation in syngeneic mice [22].

References