T cell adhesion to endothelium: the FRC conduit system and other anatomic and molecular features which facilitate the adhesion cascade in lymph node

Abstract

Since T cell surveillance depends on movement from blood into tissue and back again, rapid, efficient and selective T cell adhesion to vascular endothelium is essential. This adhesion involves a multistep cascade clarified by a recent consensus model: (1) initial tethering by selectin-mediated interactions; (2) triggering of adhesive function of T cell integrins by ligands at or near the endothelial surface; and (3) strong adhesion mediated by T cell integrins. We recapitulate this model, particularly as it pertains to the lymph node, and explore additional molecular and anatomic elements which contribute to the effectiveness of the adhesion cascades at that site: (1) importance of cytokines/soluble mediators as triggering ligands; (2) role of glycocalyx and proteoglycans on high endothelial venule (HEV) endothelium in capturing and presenting triggering cytokines; (3) remarkable function of what we designate the 'fibroblastic reticular cell (FRC) conduit system' in rapidly transporting cytokines to the HEV; (4) importance of the unique anatomy of the flap-valve junctions between HEV endothelium in enabling intravasation of cytokines and transmigration of lymphocytes. Taken together, these molecular mechanisms and these three anatomic features of lymph node facilitate extremely efficient lymphocyte traffic to this site critical for T cell-mediated immune responses. Analogous mechanisms contribute to T cell interaction with endothelium at other sites.