Inhibition of antigen-specific T cell trafficking into the central nervoussystem via blocking PECAM1/CD31 molecule

Trafficking of antigen-specific T cells into the central nervous system (CN S) is an important initiating step in inflammation in the brain. In spite o f the extensive knowledge about the role of adhesion molecules in T cell mi gration across peripheral vessels, the mechanism of the entry of antigen-sp ecific T cells into the CNS is not known. This work was designed to study t he regulatory roles of adhesion molecules in antigen-specific T cell migrat ion into the CNS. Antigen-specific T cells were tracked in an in vivo migra tion assay using T cell receptor (TCR) transgenic mice having 95% of T cell s specific for a defined antigen, pigeon cytochrome c (PCC). TCR transgenic mice were cannulated intraventricularly (IVT) for PCC antigen infusion and cerebrospinal fluid (CSF) sampling. Upon PCC infusion into the CNS. the nu mber of alpha/beta TCR+ V beta (3+) Mac1(-)cells in the CSF was characteriz ed in the presence or absence of anti-adhesion molecule reagents. We found that antibodies against VCAM-1 (CD106). VLA-4 (CD49d/CD29), ICAM-1 (CD54). and LFA-l (CD11a/CD18) did not influence the increased number of antigen-sp ecific T cells in the CSF However, upon intravenous (IV) injection, anti-PE CAM-1 (CD31) antibody or PECAM-Ig chimeric molecule inhibited the trafficki ng of alpha/beta TCR+ V beta (3+) Mac I - cells into the CNS. The expressio n of PECAM-I (CD31) was also up-regulated on antigen-specific T cells in a time-dependent manner in vitro upon antigenic stimulation. The antigen-indu ced activation of T cells in vivo was measured by CD44 and LFA-I expression and found to be comparable between mPECAMIg-treated mice and wild-type ser -um control-treated groups. This indicates that CD31 inhibition of antigen- specific T cell accumulation in the CNS is probably not due to a functional inhibition of these cells. Finally, adoptive transfer of CFSE-labeled AND transgenic cells into naive animals resulted in the accumulation of these c ells in the CNS upon PCC IVT immunization that was also inhibited by mPECAM Ig treatment. Hence, PECAM-1 (CD31) might play an important role in regulat ing antigen-specific T cells trafficking in CNS inflammatory diseases.