CELL-ADHESION AND MIGRATION ARE REGULATED AT DISTINCT STAGES OF THYMIC T-CELL DEVELOPMENT - THE ROLES OF FIBRONECTIN, VLA4, AND VLA5

T cell development in the thymus requires the establishment of stable interactions with cell-selecting elements such as the cortical epithel ium followed by a regulated movement of selected progenitors to the me dulla. Cell adhesion and migration are mediated by integrins in a numb er of biological systems though little is known regarding their functi on in the thymus. We demonstrated previously that immature CD3(lo)CD69 (lo) double positive human thymocytes adhere avidly to FN via the inte grin, VLA4. We now demonstrate that the interaction of mature CD3(hi)C D69(hi) thymic subsets with FN triggers migration rather than firm adh esion. Migration requires the engagement of VLA4 in cooperation with V LA5 and both receptors regulate the persistence and directionality of movement. While migration capability is linked to maturation state, li gand concentration determines the efficiency of migration. In fact, FN and the alternatively spliced CSI site are predominant in the thymic medulla, suggesting all instructive role of this ECM protein in vivo. Our studies identify a novel VLA4 and VLA5/FN-mediated pathway likely to be involved in regulating cell traffic between the cortex and medul la of the thymus. Moreover, tile data provides evidence that VLA4 exis ts in at least two functional states at distinct stages of T cell deve lopment. While different states of VLA4 activation have been described on cell lines, this represents the first evidence supporting a biolog ical significance for this integrin property.