Immune cell infiltration to the central nervous system (CNS) is a hallmark of the disease Multiple Sclerosis (MS). In MS, BBB dysfunction is associated with increased expression of adhesion molecules and chemokines leading to increased leukocyte trafficking to the CNS. The reciprocal attachment of leukocytes to BBB endothelial cells (BBB-ECs) is a key step of this CNS infiltration. Cell adhesion molecules (CAM) of the of the immunoglobulin family (ICAM-1 and VCAM) are key players in the interactions between the immune cells and the BBB-ECs. To describe novel CAMs of the BBB we used a lipid raft-based proteomic approach to identify an immunoglobulin subfamily of proteins expressed by BBB-ECs. Melanoma cell adhesion molecule (MCAM/CD146) was identified in this screen and this project aims to characterize MCAM's function in immune cell migration across the BBB. Our data demonstrates that MCAM is expressed on the surface of BBB-ECs, in vitro and in situ and co-localizes with lymphocyte surface markers during adhesion and diapedesis. Since MCAM's only known ligand is MCAM itself, we analysed MCAM expression on peripheral blood leukocytes from human healthy donors and MS patients. MCAM was detected on a unique subset of effector memory CD4+and CD8+T lymphocytes. In vitro polyclonal activation induced MCAM up-regulation on T lymphocytes. Moreover, we found that MCAM+T lymphocytes produce significantly more inflammatory cytokines interferon-gamma and IL-17 compared to MCAMneg cells. Finally, the proportion of MCAM+T cells was found to be consistently higher in MS patients during relapses compared to non-relapsing patients and controls. Our data indicates that MCAM is expressed by both the BBB and peripheral blood immune cells and suggests that MCAM could play an important role in CNS inflammatory reactions, including MS.