The cutaneous lymphocyte-associated Ag (CLA) is expressed by a subset of circulating memory/effector T cells and by the vast majority of skin-infiltrating T cells. CLA is thought to target skin-associated T cells to inflammatory skin sites by interacting with endothelial cell ligand E-selectin (CD62E). We have examined adhesion molecules involved in the migration of human CLA+ and CLA- memory/effector T lymphocytes through IL-1- and TNF-alpha-activated and nonactivated HUVEC layers under static (nonflow) conditions. CLA-enriched memory/effector T lymphocytes migrated more actively across cytokine-activated HUVEC than CLA-depleted memory/effector T cells. This enhanced migration is dependent on the CLA/E-selectin interaction. mAb to very late Ag-4 (VLA-4) and vascular cell adhesion molecule-1 (VCAM-1) blocked the migration of CLA-enriched, but not of CLA-depleted, T cells across activated HUVEC. The observation that anti-VLA-4 and anti-CLA mAb did not show additional inhibition supports the concept that CLA and VLA-4 are sequentially involved in the extravasation. The fact that only CLA+ T cells were inhibited by the anti-VLA-4 mAb suggests that, in this system, CLA engagement is required for using the VLA-4/VCAM-1 pathway. Our studies demonstrate that CLA+ T cells use LFA-1/intercellular leukocyte adhesion molecule-1 (ICAM-1) for transmigration but that CLA expression is not required for the LFA-1/ICAM-1-dependent transmigration because anti-CD18/CD11a mAbs and anti-ICAM-1 mAbs were able to block T cell migration regardless of the activation state of HUVEC or the CLA expression by T cells. Taken together, our results suggest that CLA has a homing function in conducting the T cell to interact with LFA-1/ICAM-1 and/or VLA-4/VCAM-1; this results in enhanced adhesion and migration across cytokine-activated endothelial cells.