Abstract
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.
Original language | English |
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Pages (from-to) | 699-711 |
Number of pages | 13 |
Journal | Acta Neuropathologica |
Volume | 127 |
Issue number | 5 |
DOIs | |
Publication status | Published - May 2014 |
Keywords
- ATP Binding Cassette Transporter, Subfamily B/genetics
- Animals
- Blood-Brain Barrier/physiology
- Brain/blood supply
- CD4-Positive T-Lymphocytes/physiology
- CD8-Positive T-Lymphocytes/physiology
- Cell Line
- Chemokine CCL2/genetics
- Encephalomyelitis, Autoimmune, Experimental/immunology
- Female
- Humans
- Mice, Inbred C57BL
- Mice, Knockout
- Microvessels/pathology
- Multiple Sclerosis/immunology
- Transendothelial and Transepithelial Migration/physiology