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

Acta Neuropathol. 2014 May;127(5):699-711. doi: 10.1007/s00401-014-1244-8. Epub 2014 Jan 16.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B / metabolism*
  • Animals
  • 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
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microvessels / pathology
  • Microvessels / physiopathology
  • Multiple Sclerosis / immunology*
  • Multiple Sclerosis / pathology
  • Transendothelial and Transepithelial Migration / physiology*

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • CCL2 protein, human
  • Ccl2 protein, mouse
  • Chemokine CCL2
  • P-glycoprotein 2
  • multidrug resistance protein 3