Lymphatic Endothelial Cell Activation and Dendritic Cell Transmigration Is Modified by Genetic Deletion of Clever-1.

Sina Tadayon,Akira Takeda,Dominik Eichin,Johannes Dunkel,Reetta Virtakoivu,Sirpa Jalkanen,Kati Elima,Maija Hollmén

doi:10.3389/fimmu.2021.602122

Abstract

Clever-1 also known as Stabilin-1 and FEEL-1 is a scavenger molecule expressed on a subpopulation of anti-inflammatory macrophages and lymphatic endothelial cells (LECs). However, its role in regulating dendritic cell (DC) trafficking and subsequent effects on immunity have remained unexplored. In this study, we demonstrate that DC trafficking from the skin into the draining lymph nodes is compromised in the absence of Clever-1. By adoptive transfer approaches we further show that the poor trafficking is due to the impaired entrance of DCs into afferent lymphatics. Despite this, injections of ovalbumin-loaded DCs into the footpads induced a stronger proliferative response of OT II T cells in the draining lymph nodes. This could be explained by the increased MHC II expression on DCs and a less tolerogenic phenotype of LECs in lymph nodes of Clever-1 knockout mice. Thus, although fewer DCs reach the nodes, they are more active in creating antigen-specific immune responses. This suggests that the DCs migrating to the draining lymph node within Clever-1 positive lymphatics experience immunosuppressive interactions with LECs. In conclusion, besides being a trafficking molecule on lymphatic vasculature Clever-1 is immunosuppressive towards migrating DCs and thus, regulates the magnitude of immune responses created by incoming DCs in the draining lymph nodes.

Highlights

To initiate an effective adaptive immune response or tolerance, dendritic cells (DCs) among other leukocytes, migrate from the periphery to the draining lymph nodes via the afferent lymphatic vessels
lymphatic endothelial cells (LECs) of LNs lacking Clever-1 has a more proinflammatory phenotype than their wild type (WT) controls at steady state, explaining the normal level of the antigen-specific immune response, despite impaired DC trafficking into the draining lymph nodes (dLNs)
A greater number of bone marrowderived dendritic cells (BMDC) adhered on the ear lymphatics of KO mice after 2 h suggesting that the impairment in DC trafficking into the dLNs was not due to blockage of intra-lymphatic migration but rather in the entrance of DCs to lymphatic vessels (Figure 3B)

Summary

Introduction

To initiate an effective adaptive immune response or tolerance, dendritic cells (DCs) among other leukocytes, migrate from the periphery to the draining lymph nodes (dLNs) via the afferent lymphatic vessels. DC trafficking from the periphery to the draining lymph nodes through lymphatic vessels and their ability to carry and present antigens in the node is an essential element in the induction of the immune response within the lymph nodes [1,2,3,4]. Lymphatic Clever-1 Regulates Dendritic Cells have been identified to be responsible for dendritic cell migration within the afferent lymphatics. They include sphingosine 1 phosphate, CD31, CD99, Semaphorin 3A, Podoplanin, LYVE1, and chemokines such as CCL21 and CXCL12. Even though LECs do not express co-stimulatory molecules such as 41BBL, CD86, and CD80, they endocytose antigens, cross-present MHC I antigens and express PD-L1 and MHC II molecules [4]

Methods

Results

Conclusion