Regulation of Dendritic Cell Migration to the Draining Lymph Node

Abstract

Antigen-pulsed dendritic cells (DCs) are used as natural adjuvants for vaccination, but the factors that influence the efficacy of this treatment are poorly understood. We investigated the parameters that affect the migration of subcutaneously injected mouse-mature DCs to the draining lymph node. We found that the efficiency of DC migration varied with the number of injected DCs and that CCR7+/+ DCs migrating to the draining lymph node, but not CCR7−/− DCs that failed to do so, efficiently induced a rapid increase in lymph node cellularity, which was observed before the onset of T cell proliferation. We also report that DC migration could be increased up to 10-fold by preinjection of inflammatory cytokines that increased the expression of the CCR7 ligand CCL21 in lymphatic endothelial cells. The magnitude and quality of CD4+ T cell response was proportional to the number of antigen-carrying DCs that reached the lymph node and could be boosted up to 40-fold by preinjection of tumor necrosis factor that conditioned the tissue for increased DC migration. These results indicate that DC number and tissue inflammation are critical parameters for DC-based vaccination.

Distinct in vivo dendritic cell activation by live versus killed Listeria monocytogenes

“…Activated B cells have been shown to move to the T cell zones in secondary lymphoid organs by up-regulating CCR7 expression, enabling chemotaxis towards CCL19 and CCL21 [20]. Along similar lines, DC also up-regulate CCR7 upon exposure to inflammatory stimuli, which enables trafficking to splenic and lymph node T cell zones [21,22]. Therefore, Listeria-infected cells might express CCR7 upon cytosolic invasion by L. monocytogenes and thus become responsive to splenic CCL19 and/or CCL21 chemokines gradients.…”

Synergy‐inducing chemokines enhance CCR2 ligand activities on monocytes

“…Most leukocytes express more than one chemokine receptor and, hence, can respond to more than one chemokine. Additionally, a great variety of in situ experiments demonstrated the concomitant expression of chemokines at target sites of leukocyte trafficking and homing [16][17][18][19][20][21].…”

“…Most leukocytes express more than one chemokine receptor and, hence, can respond to more than one chemokine. Additionally, a great variety of in situ experiments demonstrated the concomitant expression of chemokines at target sites of leukocyte trafficking and homing [16][17][18][19][20][21].Many chemokines, apart from being agonistic for their receptors, were shown to act as natural antagonists on one or several receptors in vitro and in vivo [22]. Naturally occurring N-terminal truncations of chemokines have been identified in vivo [23] and numerous enzymes were shown to generate truncations of chemokines that render them less active or inactive [24,25].…”

“…Even though an in vitro migration assay is far from reproducing the pathological environment during the initial phase of an inflammatory response, it has indicated 300 nM CCL21 as the concentration necessary for inducing a detectable synergism with 1 nM CCL7 on monocytes. CCL21 has been shown to be induced in the skin upon injection of pro-inflammatory cytokines [18] and in contact dermatitis [19], where the concomitant presence of the CCR2 agonists and CCL21 could mediate an elevated recruitment of CCR2 1 cells.Extravasation into the underlying tissue involves the degradation of the basal membrane by proteolytic enzymes. We show that the release of degrading enzymes by monocytes is strongly augmented in an environment rich in non-ligand chemokines and could therefore contribute to a faster and more efficient way of recruiting monocytes from the blood stream into lymphoid organs under inflammatory conditions.…”

Augmentation of the migratory ability of DC-based vaccine into regional lymph nodes by efficient CCR7 gene transduction

“…[5][6][7] Owing to these properties, TAA-loaded DCs are considered promising vaccine carriers in immune intervention strategies against cancer. However, very few DCs in currently available DC-based immunotherapies are capable of migrating from an administration site to regional lymphoid tissue, [16][17][18] where they present MHC class I-and II-restricted peptides to naive T cells, because optimal DC conditioning for enhancing migratory ability is not yet established. Therefore, increasing the migratory ability of a DC vaccine toward lymphoid tissues would remarkably improve the efficacy of DC-based immunotherapy because priming/activation of immune effector cells would be significantly promoted.…”