Nectin-3 (CD113) Interacts with Nectin-2 (CD112) to Promote Lymphocyte Transendothelial Migration

Elisabeth Devilard,Luc Xerri,Marc Lopez,Patrice Dubreuil,Nicolas Reymond

doi:10.1371/journal.pone.0077424

Abstract

Lymphocyte trafficking and migration through vascular endothelial cells (ECs) in secondary lymphoid tissues is critical for immune protection. In the present study, we investigate the role of nectin cell adhesion molecules for the migration of lymphocytes through ECs. Nectins are key players for the establishment of homotypic and heterotypic cell to cell contacts; they are required for cell to cell adherens junction formation and take part in the transendothelial migration of monocytes during the step of diapedesis, when monocytes migrate through EC junctions. We first show that Nectin-3 (CD113) is the only nectin expressed by T lymphocytes and since nectins are expressed on ECs we explored Nectin-3 potential functions in lymphocyte: EC interactions. We demonstrate that Nectin-2, expressed on ECs, is the major counter-receptor of Nectin-3. A soluble form of Nectin-3 binds to Nectin-2 localized at EC junctions and blocking Nectin-2 trans-interactions with monoclonal antibodies abolishes the binding of soluble Nectin-3 to ECs. Nectin-2 is expressed on High Endothelial venules (HEVs), where lymphocyte homing occurs in vivo. Finally, we show that Nectin-3 trans-interaction with Nectin-2 is essential for the process of lymphocyte transendothelial migration in vitro as targeting with blocking monoclonal antibodies either Nectin-3, expressed on lymphocytes, or Nectin-2, expressed on ECs, inhibits lymphocyte extravasation. The nectin family of CAMs is important for the regulation of endothelial barrier functions and transendothelial migration of immune cells. Our results demonstrate for the first time that Nectin-3 trans-interacts with Nectin-2 to promote lymphocyte and monocyte extravasation.

Highlights

The vascular endothelium consists of a continuous monolayer of cells that lines the entire vascular system
Using in house anti-Nectins’ Monoclonal antibodies (mAbs) that we previously characterized to be specific, we further investigated the expression of Nectins on primary endothelial cells (ECs): FACS analyses showed that Nectin-1 and Nectin-3 are expressed on human umbilical vein endothelial cells (HUVECs) while Nectin-4 is not (Figure 2A and data not shown)
As Nectin-3 is expressed on lymphocytes and soluble Nectin-3 binds to Nectin-2 expressed at EC junctions, we investigated whether the direct trans-interaction between Nectin-3 and -2 plays a role during the lymphocyte extravasation process to the interaction between DNAM-1 and endothelial PVR during monocyte extravasation [16]

Summary

Introduction

The vascular endothelium consists of a continuous monolayer of cells that lines the entire vascular system. Endothelial junctional complexes are important to control endothelial permeability and create a check-point to regulate the transmigration of large cells such as leukocytes, from the bloodstream to secondary lymphoid organs or underlying tissues [1,2,3,4,5,6,7]. Leukocytes leave the bloodstream by interacting with ECs of the vessel walls, through a well-characterized multi-step adhesion molecule cascade [1]. As the molecular bases that control lymphocyte migration within EC junctions or diapedesis are still largely unknown, the identification of new molecules involved in this process is an important field of research

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Discussion

Conclusion