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

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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.

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Abbreviations

ATP:

Adenosine triphosphate

CCL2:

Chemokine (C–C motif) ligand 2

EAE:

Experimental autoimmune encephalomyelitis

TNF-α:

Tumor necrosis factor-α

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Acknowledgments

We thank the Netherlands Brain Bank for providing human brain tissues and Dr. Shujun Ge who provided the endothelial CCL2−/− mice. This work was supported by grants 016.046.314 from the Netherlands Organization of Scientific Research, and MS 08-652 from the Dutch foundation of Multiple Sclerosis Research, to G. Kooij; and Grants R0-1-MH061525 from the National Institutes of Health, and PP-1215 and RG 4828-A-5 from the National Multiple Sclerosis Society, to J.S. Pachter.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. 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

    Gijs Kooij, Arie Reijerkerk, Susanne M. A. van der Pol, Bert van het Hof, Joost A. Drexhage, Sandra J. van Vliet & Helga E. de Vries

  2. Sanquin Research and Landsteiner Laboratory, Department of Molecular Cell Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Jeffrey Kroon & Jaap D. van Buul

  3. Blood-Brain Barrier Laboratory, Department of Cell Biology, University of Connecticut Health Center, Farmington, USA

    Debayon Paul & Joel S. Pachter

  4. Department of Pediatric Oncology/Hematology, Sophia Children’s Hospital, Erasmus University Medical Center, Rotterdam, The Netherlands

    Dirk Geerts

  5. Department of Biomolecular Imaging, Institute of Biomembranes, University Utrecht, Utrecht, The Netherlands

    Liesbeth H. P. Hekking

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  1. Gijs Kooij
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Correspondence to Gijs Kooij.

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Kooij, G., Kroon, J., Paul, D. et al. P-glycoprotein regulates trafficking of CD8+ T cells to the brain parenchyma. Acta Neuropathol 127, 699–711 (2014). https://doi.org/10.1007/s00401-014-1244-8

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