Circulating lymphocytes continuously enter lymph nodes for immune surveillance through specialized blood vessels named high endothelial venules, a process that increases markedly during immune responses. How high endothelial venules (HEVs) permit lymphocyte transmigration while maintaining vascular integrity is unknown. Here we report a role for the transmembrane O-glycoprotein podoplanin (PDPN, also known as gp38 and T1α) in maintaining HEV barrier function. Mice with postnatal deletion of Pdpn lost HEV integrity and exhibited spontaneous bleeding in mucosal lymph nodes, and bleeding in the draining peripheral lymph nodes after immunization. Blocking lymphocyte homing rescued bleeding, indicating that PDPN is required to protect the barrier function of HEVs during lymphocyte trafficking. Further analyses demonstrated that PDPN expressed on fibroblastic reticular cells, which surround HEVs, functions as an activating ligand for platelet C-type lectin-like receptor 2 (CLEC-2, also known as CLEC1B). Mice lacking fibroblastic reticular cell PDPN or platelet CLEC-2 exhibited significantly reduced levels of VE-cadherin (also known as CDH5), which is essential for overall vascular integrity, on HEVs. Infusion of wild-type platelets restored HEV integrity in Clec-2-deficient mice. Activation of CLEC-2 induced release of sphingosine-1-phosphate from platelets, which promoted expression of VE-cadherin on HEVs ex vivo. Furthermore, draining peripheral lymph nodes of immunized mice lacking sphingosine-1-phosphate had impaired HEV integrity similar to Pdpn- and Clec-2-deficient mice. These data demonstrate that local sphingosine-1-phosphate release after PDPN-CLEC-2-mediated platelet activation is critical for HEV integrity during immune responses.
|Number of pages||5|
|State||Published - 2013|
Bibliographical noteFunding Information:
Acknowledgements We thank P. Kincade and L. Thompson for critical reading of the manuscript; R. Adams for providing PdgfrbCre mice; and M. Kinter and M.C. Marlin for technical assistance. Work was supported by grants from the National Institutes of Health (GM103441, GM097747, HL085607, HL093242, HL103432, HL065590, HL112788), VA Merit Award (BX001984), the American Heart Association (SDG7410022), the Deutsche Forschungsgemeinschaft (SFB688), National Natural Science Foundation of China (30928010), Jiangsu Provincial Special Program of Medical Science (BL2012005) and Jiangsu Province’s Key Medical Center (ZX201102).
ASJC Scopus subject areas