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

Autor: Kooij G; Blood-Brain Barrier Research Group, Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands, g.kooij@vumc.nl., Kroon J, Paul D, Reijerkerk A, Geerts D, van der Pol SM, van Het Hof B, Drexhage JA, van Vliet SJ, Hekking LH, van Buul JD, Pachter JS, de Vries HE
Jazyk: angličtina
Zdroj: Acta neuropathologica [Acta Neuropathol] 2014 May; Vol. 127 (5), pp. 699-711. Date of Electronic Publication: 2014 Jan 16.
DOI: 10.1007/s00401-014-1244-8
Abstrakt: 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.
Databáze: MEDLINE
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