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

Gijs Kooij, Jeffrey Kroon, Debayon Paul, Arie Reijerkerk, Dirk Geerts, Susanne M A van der Pol, Bert van Het Hof, Joost A Drexhage, Sandra J van Vliet, Liesbeth H P Hekking, Jaap D van Buul, Joel S Pachter, Helga E de Vries

Research output: Contribution to journalArticleAcademicpeer-review

24 Citations (Scopus)


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 languageEnglish
Pages (from-to)699-711
Number of pages13
JournalActa Neuropathologica
Issue number5
Publication statusPublished - May 2014


  • 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

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