P-glycoprotein regulates trafficking of CD8+ T cells to the brain parenchyma

• Published in: Acta neuropathologica Vol. 127; no. 5; pp. 699 - 711
• Main Authors: Kooij, Gijs, Kroon, Jeffrey, Paul, Debayon, Reijerkerk, Arie, Geerts, Dirk, van der Pol, Susanne M. A., van het Hof, Bert, Drexhage, Joost A., van Vliet, Sandra J., Hekking, Liesbeth H. P., van Buul, Jaap D., Pachter, Joel S., de Vries, Helga E.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.05.2014
• Subjects: Animals; ATP Binding Cassette Transporter, Subfamily B - genetics; ATP Binding Cassette Transporter, Subfamily B - metabolism; ATP-Binding Cassette Sub-Family B Member 4; Blood-Brain Barrier - physiology; Brain - blood supply; Brain - immunology; Brain - pathology; CD4-Positive T-Lymphocytes - physiology; CD8-Positive T-Lymphocytes - physiology; Cell Line; Chemokine CCL2 - genetics; Chemokine CCL2 - metabolism; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - pathology; Female; Humans; Medicine; Medicine & Public Health; Mice, Inbred C57BL; Mice, Knockout; Microvessels - pathology; Microvessels - physiopathology; Multiple Sclerosis - immunology; Multiple Sclerosis - pathology; Neurosciences; Original Paper; Pathology; Transendothelial and Transepithelial Migration - physiology; P-glycoprotein; Multiple sclerosis; CD8; Neuro-immunology; CCL2; Transendothelial migration; T cells
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-014-1244-8

The trafficking of cytotoxic CD8 + T lymphocytes across the lining of the cerebral vasculature is key to the onset of the chronic neuro-inflammatory disorder multiple sclerosis. However, the mechanisms controlling their final transmigration across the brain endothelium remain unknown. Here, we describe that CD8 + T lymphocyte trafficking into the brain is dependent on the activity of the brain endothelial adenosine triphosphate-binding cassette transporter P-glycoprotein. Silencing P-glycoprotein activity selectively reduced the trafficking of CD8 + T cells across the brain endothelium in vitro as well as in vivo. In response to formation of the T cell–endothelial synapse, P-glycoprotein was found to regulate secretion of endothelial (C–C motif) ligand 2 (CCL2), a chemokine that mediates CD8 + T cell migration in vitro. Notably, CCL2 levels were significantly enhanced in microvessels isolated from human multiple sclerosis lesions in comparison with non-neurological controls. Endothelial cell-specific elimination of CCL2 in mice subjected to experimental autoimmune encephalomyelitis also significantly diminished the accumulation of CD8 + T cells compared to wild-type animals. Collectively, these results highlight a novel (patho)physiological role for P-glycoprotein in CD8 + T cell trafficking into the central nervous system during neuro-inflammation and illustrate CCL2 secretion as a potential link in this mechanism.