Roles of alpha(4) integrins/VCAM-1 and LFA-1/ICAM-1 in the binding and transendothelial migration of T lymphocytes and T lymphoblasts across high endothelial venules

Several cell adhesion molecules that mediate the binding of lymphocytes to high endothelial venules (HEV) from flowing blood have been identified but the regulation of lymphocyte migration across the HEV wall into the lymph n ode (LN) is far from understood. In this study we have used an in vitro mod el of lymphocyte migration across HEV, and analysed the roles of two integr ins in the binding and transendothelial migration of T lymphocytes and T ly mphoblasts, The adhesion of T lymphocytes to high endothelial cells (HEC) c ultured from rat LN HEV differed from that of T lymphoblasts since the perc entage of T lymphoblasts that adhered and transmigrated was higher and was not increased by IFN-gamma pretreatment of HEC. Antibodies to alpha(4) inte grins, VCAM-1 or LFA-1 maximally inhibited T lymphocyte adhesion by 40-50%, whereas antibodies to ICAM-1 were less effective (<20% inhibition). The ef fects of alpha(4) integrin and LFA-1 antibodies were additive, giving >90% inhibition. T lymphocytes which adhered in the presence of LFA-1 antibody s howed reduced levels of transmigration and, in the presence of alpha(4) int egrin antibody, slightly increased transmigration. Antibodies to a4 integri ns, VCAM-1, LFA-1 or ICAM-1 had little effect on T lymphoblast adhesion (ma xima of 10-30% inhibition) and T lymphoblasts transmigrated normally in the presence of either alpha(4) integrin or LFA-1 antibodies. However, the eff ects of alpha(4) integrin and LFA-1 antibodies on T lymphoblast adhesion we re synergistic, giving >90% inhibition of adhesion. These results suggest t hat the majority of T lymphoblasts use either alpha(4) integrins or LFA-1 t o bind and transmigrate HEV, and the roles of these integrins on activated T cells are overlapping and redundant. In contrast, either integrin support s half-maximal binding of unactivated T lymphocytes to the surface of HEV a nd LFA-1 makes a larger contribution than alpha(4) integrins to transendoth elial migration.