MIGRATION OF SKIN-HOMING T-CELLS ACROSS CYTOKINE-ACTIVATED HUMAN ENDOTHELIAL-CELL LAYERS INVOLVES INTERACTION OF THE CUTANEOUS LYMPHOCYTE-ASSOCIATED ANTIGEN (CLA), THE VERY LATE ANTIGEN-4 (VLA-4), AND THE LYMPHOCYTE FUNCTION-ASSOCIATED ANTIGEN-1 (LFA-1)

The cutaneous lymphocyte-associated Ag (CLA) is expressed by a subset of circulating memory/effector T cells and by the vast majority of ski n-infiltrating T cells. CLA is thought to target skin-associated T cel ls to inflammatory skin sites by interacting with endothelial cell lig and E-selectin (CD62E). We have examined adhesion molecules involved i n the migration of human CLA(+) and CLA(-) memory/effector T lymphocyt es through IL-1- and TNF-alpha-activated and nonactivated HUVEC layers under static (nonflow) conditions. CLA-enriched memory/effector T lym phocytes migrated more actively across cytokine-activated HUVEC than C LA-depleted memory/effector T cells. This enhanced migration is depend ent on the CLA/E-selectin interaction. mAb to very late Ag-4 (VLA-4) a nd 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 additi onal inhibition supports the concept that CLA and VLA-4 are sequential ly involved in the extravasation. The fact that only CLA(+) T cells we re inhibited by the anti-VLA-4 mAb suggests that, in this system, CIA engagement is required for using the VLA-4/VCAM-1 pathway. Our studies demonstrate that CLA(+) T cells use LFA-1/intercellular leukocyte adh esion molecule-1 (ICAM-1) for transmigration but that CLA expression i s not required for the LFA-1/ICAM-1-dependent transmigration because a nti-CD18/CD11a mAbs and anti-ICAM-1 mAbs were able to block T cell mig ration regardless of the activation state of HUVEC or the CLA expressi on by T cells. Taken together, our results suggest that CLA has a homi ng 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 acro ss cytokine-activated endothelial cells.