Dendritic cells adhere to and transmigrate across lymphatic endothelium in response to IFN‐α

Abstract

Migration of DC into lymphatic vessels ferries antigenic cargo and pro-inflammatory stimuli into the draining LN. Given that tissues under the influence of viral infections produce type I IFN, it is conceivable that these cytokines enhance DC migration in order to facilitate an antiviral immune response. Cultured lymphatic endothelium monolayers pretreated with TNF-a were used to model this phenomenon under inflammatory conditions. DC differentiated in the presence of either IFN-a2b or IFN-a5 showed enhanced adhesion to cultured lymphatic endothelial cells. These pro-adhesive effects were mediated by DC, not the lymphatic endothelium, and correlated with increased DC transmigration across lymphatic endothelial cell monolayers. Transmigration was guided by chemokines acting on DC, and blocking experiments with mAb indicated a role for LFA-1. Furthermore, incubation of DC with IFN-a led to the appearance of active conformation epitopes on the CD11a integrin chains expressed by DC. Differentiation of mouse DC in the presence of IFN-a also increased DC migration from inflammed footpads toward popliteal LN. Collectively, these results indicate a role for type I IFN in directing DC toward LN under inflammatory conditions.

Lymphatic Endothelium Forms Integrin-Engaging 3D Structures during DC Transit across Inflamed Lymphatic Vessels

“…In fact, we and others have demonstrated that integrin ligands are induced on lymphatic endothelial cells under inflammation. Indeed, the inhibition of integrin ligands in mice significantly reduced the number of exogenously injected DCs that reached the lymph nodes under inflammation (Johnson and Jackson, 2008;Podgrabinska et al, 2009;Rouzaut et al, 2010).…”

“…An increasing number of reports have demonstrated the upregulation of adhesive molecules such as E-selectin and the integrin ligands ICAMs and vascular cell adhesion molecule-1 (VCAM) on lymphatic endothelial cells (LECs) under inflammation Jackson, 2010, Vigl et al, 2011). Furthermore, we and others have demonstrated how b2 and b1 integrin blockade decreases DC migration to the lymph nodes under inflammatory conditions (Podgrabinska et al, 2009, Rouzaut et al, 2010, Nitschké et al, 2012. Interestingly, active epitopes of aLb1 (LFA-1) integrin are induced in human dendritic cells after exposure to chemokines such as CCL21 (Eich et al, 2011), produced by lymphatic endothelial cells.…”

“…Primary dermal lymphatic endothelial cells (Clonetics-Lonza, Barcelona, Spain) were grown in EGM-2MV medium (Clonetics) as described (Rouzaut et al, 2010). Cells were used at passages 5-7.…”

Direct Effects of Type I Interferons on Cells of the Immune System

“…Interestingly, experiments in mice have also shown that IFN-a/b is required for plasmacytoid DCs (pDC) to migrate from the marginal zone into the T-cell area, where they form clusters (49). We have also recently shown that IFNs-I enhance the adhesion and extravasations of DCs across inflamed lymphatic endothelium in a lymphocyte function-associated antigen 1 (LFA-1)-and very late antigen-4 (VLA4)-dependent fashion (50). IFNs-I may also favor the encounter between DCs and specific lymphocytes in lymph nodes by promoting lymphocyte trapping in lymph nodes upon downmodulation of sphingosine 1-phosphate (51).…”

Emerging roles of lymphatic endothelium in regulating adaptive immunity

“…These studies and others indicate that LECs are capable of expressing and actively signaling through a variety of cytokines and adhesion receptor-ligand interactions important in immunity (Tables 1, 2, and 3, and refs. 17,[27][28][29][30].…”