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Brain Advance Access published online on January 29, 2009
Brain, doi:10.1093/brain/awn354
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© The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Differential immune cell dynamics in the CNS cause CD4+ T cell compartmentalization

Volker Siffrin1,*, Alexander U. Brandt1,*, Helena Radbruch1,*, Josephine Herz1, Nadia Boldakowa1, Tina Leuenberger1, Johannes Werr1, Astrid Hahner1, Ulf Schulze-Topphoff1, Robert Nitsch2 and Frauke Zipp1

1 Cecilie Vogt Clinic for Neurology in the HKBB, Charité - University Medicine, Berlin and Max Delbrueck Centre for Molecular Medicine Berlin-Buch, Berlin, Germany 2 Cell and Neurobiology, Centre for Anatomy, Charité - University Medicine Berlin, Germany

Correspondence to: Prof Dr Frauke Zipp, Cecilie Vogt Clinic for Neurology in the HKBB, Charité - University Medicine Berlin and Max Delbrueck Centre for Molecular Medicine, Charitéplatz 1, 10117 Berlin, Germany E-mail: frauke.zipp{at}charite.de

In the course of autoimmune CNS inflammation, inflammatory infiltrates form characteristic perivascular lymphocyte cuffs by mechanisms that are not yet well understood. Here, intravital two-photon imaging of the brain in anesthetized mice, with experimental autoimmune encephalomyelitis, revealed the highly dynamic nature of perivascular immune cells, refuting suggestions that vessel cuffs are the result of limited lymphocyte motility in the CNS. On the contrary, vessel-associated lymphocyte motility is an actively promoted mechanism which can be blocked by CXCR4 antagonism. In vivo interference with CXCR4 in experimental autoimmune encephalomyelitis disrupted dynamic vessel cuffs and resulted in tissue-invasive migration. CXCR4-mediated perivascular lymphocyte movement along CNS vessels was a key feature of CD4+ T cell subsets in contrast to random motility of CD8+ T cells, indicating a dominant role of the perivascular area primarily for CD4+ T cells. Our results visualize dynamic T cell motility in the CNS and demonstrate differential CXCR4-mediated compartmentalization of CD4+ T-cell motility within the healthy and diseased CNS.

Key Words: T cells; compartmentalization; two-photon microscopy; CXCR4; EAE/MS

Abbreviations: ACSF, artificial cerebrospinal fluid; EAE, experimental autoimmune encephalomyelitis; FRC, fibroblastic reticular cells; IVC, individually ventilated cages; OCT, optimum cutting temperature; PBMC, peripheral blood mononuclear cells; SPF, specifically pathogen free

.

Received July 23, 2008. Revised November 18, 2008. Accepted December 3, 2008.

*These authors contributed equally to this work.


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