Intralymphatic CCL21 Promotes Tissue Egress of Dendritic Cells through Afferent Lymphatic Vessels

Abstract

To induce adaptive immunity, dendritic cells (DCs) migrate through afferent lymphatic vessels (LVs) to draining lymph nodes (dLNs). This process occurs in several consecutive steps. Upon entry into lymphatic capillaries, DCs first actively crawl into downstream collecting vessels. From there, they are next passively and rapidly transported to the dLN by lymph flow. Here, we describe a role for the chemokine CCL21 in intralymphatic DC crawling. Performing time-lapse imaging in murine skin, we found that blockade of CCL21-but not the absence of lymph flow-completely abolished DC migration from capillaries toward collecting vessels and reduced the ability of intralymphatic DCs to emigrate from skin. Moreover, we found that in vitro low laminar flow established a CCL21 gradient along lymphatic endothelial monolayers, thereby inducing downstream-directed DC migration. These findings reveal a role for intralymphatic CCL21 in promoting DC trafficking to dLNs, through the formation of a flow-induced gradient.

Vascular, glial, and lymphatic immune gateways of the central nervous system

“…These two factors induce the migration of DCs into lymphatic vessels by engaging the CCR7 ligand CCL21 specifically expressed by lymphatic endothelial cells. DCs first crawl along the lymphatic endothelium using specific adhesive interactions, e.g., the cytokine CCL21, before they detach and are passively transported to the regional lymph nodes in the larger calibre lymphatic vessels [97, 115]. Once they have arrived in the lymph node, DCs activate antigen-specific T cells that in turn proliferate and reach the blood stream via the efferent lymphatic vessels.…”

What Do Structures Tell Us About Chemokine Receptor Function and Antagonism?

“…By contrast, oligomerization is required for high affinity binding of chemokines to their “other receptors”, the glycosaminoglycans (GAGs), which are found on cell surfaces and the extracellular matrix (34). These GAG interactions are important for immobilizing chemokines and facilitating the formation of haptotactic chemokine gradients that effectively provide a path for chemokine receptor bearing cells to follow (49, 82, 111, 116). Thus in the multistep process of cell migration, chemokine oligomers bound to GAGs must reversibly dissociate to fully engage receptors as monomers.…”

“…The ligands (chemokines) are small proteins that are secreted by most cell types either constitutively or inducibly, in response to a wide variety of stimuli and environmental cues (110). By forming gradients on cell surfaces and extracellular matrices in tissues, chemokines serve as the directional signals for cell migration (82, 111). …”

Heterogeneity in the lymphatic vascular system and its origin

“…25 DC entry is followed by intraluminal crawling inside the lymphatic capillaries, a process which was recently described to depend on immobilized intraluminal CCL21 gradients formed in a flow-dependent manner. 26 In contrast, transfer of DCs within the collecting vessels to draining lymph nodes is thought to be passive. In addition to DCs, other immune cells including recirculating memory T-cells 27 and neutrophils 28 have been reported to enter lymphatic vessels in a CCR7-dependent manner.…”

“…The same chemokine axis CCR7–CCL21 that guides entry of DCs into peripheral lymphatic vessels 24,26 have intriguingly also been shown to be essential for their exit from the SCS into the lymph node parenchyma. 78 Whereas transendothelial channels restricted by PLVAP diaphragms in fLECs may provide a path for the lymph-borne immune cells into the lymph node, the CCR7-driven directional transit was shown to be regulated by the LECs that form the ceiling of the SCS (cLECs), dependent on their expression of the atypical chemokine receptor CCRL1 (ACKR4).…”