CCL19 and CCL21 Induce a Potent Proinflammatory Differentiation Program in Licensed Dendritic Cells

Abstract

Dendritic cells (DCs) are key instigators of adaptive immune responses. Using an alphaviral expression cloning technology, we have identified the chemokine CCL19 as a potent inducer of T cell proliferation in a DC-T cell coculture system. 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. Moreover, CCL19 programmed DCs for the induction of T helper type (Th) 1 rather than Th2 responses. 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. Migrating DCs isolated from mice genetically deficient in CCL19 and CCL21 (plt/plt) presented an only partially mature phenotype, highlighting the importance of these chemokines for full DC maturation in vivo. Our findings indicate that CCL19 and CCL21 are potent natural adjuvants for terminal activation of DCs and suggest that chemokines not only orchestrate DC migration but also regulate their immunogenic potential for the induction of T cell responses.

CCR 7 Ligands Are Required for Development of Experimental Autoimmune Encephalomyelitis through Generating IL-23-Dependent Th17 Cells

“…The decrease in the frequency of intracellular IFN-␥ ϩ CD4 ϩ T cells and in IL-12 production by DCs was recovered by the addition of exogenous CCL19 or CCL21 (Fig. 4A and data not shown), as shown previously (19), suggesting that the defect to generate MOG 35-55 -specific Th1 cells could be included in the resistance to EAE development in plt/plt mice as reported very recently (15,16). However, this possibility is unlikely since DLN cells prepared from plt/plt mice and incubated under the conditions for generating Th1 cells could not develop EAE in naive WT recipient mice, whereas those incubated under the Th17-generating conditions did develop EAE (Fig.…”

Repulsive guidance molecule a blockade exerts the immunoregulatory function in DCs stimulated with ABP and LPS

“…However, the neutralizing antibody did not have effect on CCR7, perhaps because the most important function for the chemokine is organizing DCs migration, not regulating DCs maturation or tolerance. Additionally, CCR7 can modulate DCs maturation only in activated DCs, not in immature DCs, 21 which is consistent with our study. Interestingly, we also noticed that DCs treated with RGMa-neutralizing antibody could secrete the medium levels of immunostimulatory cytokines and high levels of IL-10, unlike immature DCs.…”

CCL19 reduces tumour burden in a model of advanced lung cancer

“…Because DCs are potent APCs that function as principal activators of T cells, CCL19's capacity to facilitate the colocalisation of both DC and T cells may reverse tumour-mediated immune suppression and orchestrate effective cell-mediated immune responses. In addition, CCL19 is a potent inducer of T-cell proliferation and programmes DCs for the induction of T helper (Th) 1 rather than Th2 responses (Marsland et al, 2005). Based on these properties, we speculated that CCL19 would be an important protein for evaluation in cancer immunotherapy.…”