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.