Inhibition of antigen-specific T cell trafficking into the central nervous system via blocking PECAM1/CD31 molecule.
Trafficking of antigen-specific T cells into the central nervous system (CNS) is an important initiating step in inflammation in the brain. In spite of the extensive knowledge about the role of adhesion molecules in T cell migration across peripheral vessels, the mechanism of the entry of antigen-specific T cells into the CNS is not known. This work was designed to study the regulatory roles of adhesion molecules in antigen-specific T cell migration into the CNS. Antigen-specific T cells were tracked in an in vivo migration assay using T cell receptor (TCR) transgenic mice having 95% of T cells 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 number of alpha/beta TCR+ Vbeta3+ Mac1- cells in the CSF was characterized 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-1 (CD11a/CD18) did not influence the increased number of antigen-specific T cells in the CSF However, upon intravenous (i.v.) injection, anti-PECAM-1 (CD31) antibody or PECAM-Ig chimeric molecule inhibited the trafficking of alpha/beta TCR+ Vbeta3+ Mac1- cells into the CNS. The expression of PECAM-1 (CD31) was also up-regulated on antigen-specific T cells in a time-dependent manner in vitro upon antigenic stimulation. The antigen-induced activation of T cells in vivo was measured by CD44 and LFA-1 expression and found to be comparable between mPECAMIg-treated mice and wild-type serum 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 naïve animals resulted in the accumulation of these cells in the CNS upon PCC IVT immunization that was also inhibited by mPECAMIg treatment. Hence, PECAM-1 (CD31) might play an important role in regulating antigen-specific T cells trafficking in CNS inflammatory diseases.
Qing
Z
Z
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, 53706, USA.
Sandor
M
M
Radvany
Z
Z
Sewell
D
D
Falus
A
A
Potthoff
D
D
Muller
W A
WA
Fabry
Z
Z
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000276:immunology; D002490:Central Nervous System / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D010856:Columbidae; D000939:Epitopes; D007136:Immunoglobulins / Q000494:pharmacology; D039041:Integrin alpha4beta1; D016023:Integrins / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism*; D016201:Receptors, Lymphocyte Homing / Q000276:immunology; D012995:Solubility; D013601:T-Lymphocytes / Q000276:immunology*
D000906:Antibodies; D015815:Cell Adhesion Molecules; D000939:Epitopes; D007136:Immunoglobulins; D039041:Integrin alpha4beta1; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D016201:Receptors, Lymphocyte Homing