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Brain Advance Access originally published online on December 20, 2007
Brain 2008 131(3):785-799; doi:10.1093/brain/awm295
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© The Author (2007). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The blood–brain barrier induces differentiation of migrating monocytes into Th17-polarizing dendritic cells

Igal Ifergan, Hania Kébir, Monique Bernard, Karolina Wosik, Aurore Dodelet-Devillers, Romain Cayrol, Nathalie Arbour and Alexandre Prat

Neuroimmunology Research Laboratory, Center for the Study of Brain Diseases, CHUM-Hôpital Notre-Dame, Université de Montréal, Montréal, Québec, Canada

Correspondence to: Dr Alexandre Prat, MD, PhD, Department of Medicine (Neurology) and Immunology, Multiple Sclerosis Clinic and Neuroimmunology Research Laboratory, CHUM-Hôpital Notre-Dame and CHUM Research Center, Université de Montréal, 1560 Sherbrooke East, Montréal, Québec, Canada H2L 4M1 E-mail: a.prat{at}umontreal.ca

Trafficking of antigen-presenting cells into the CNS is essential for lymphocyte reactivation within the CNS compartment. Although perivascular dendritic cells found in inflammatory lesions are reported to polarize naive CD4+ T lymphocytes into interleukin-17-secreting-cells, the origin of those antigen-presenting cells remains controversial. We demonstrate that a subset of CD14+ monocytes migrate across the inflamed human blood–brain barrier (BBB) and differentiate into CD83+CD209+ dendritic cells under the influence of BBB-secreted transforming growth factor-β and granulocyte-macrophage colony-stimulating factor. We also demonstrate that these dendritic cells secrete interleukin-12p70, transforming growth factor-β and interleukin-6 and promote the proliferation and expansion of distinct populations of interferon-{gamma}-secreting Th1 and interleukin-17-secreting Th17 CD4+ T lymphocytes. We further confirmed the abundance of such dendritic cells in situ, closely associated with microvascular BBB-endothelial cells within acute multiple sclerosis lesions, as well as a significant number of CD4+ interleukin-17+ T lymphocytes in the perivascular infiltrate. Our data support the notion that functional perivascular myeloid CNS dendritic cells arise as a consequence of migration of CD14+ monocytes across the human BBB, through the concerted actions of BBB-secreted transforming growth factor-β and granulocyte-macrophage colony-stimulating factor.

Key Words: blood–brain barrier; dendritic cells; multiple sclerosis; IL-17; CNS

Abbreviations: BBB, blood–brain barrier; MHC, major histocompatibility complex; EAE, experimental autoimmune encephalomyelitis; TNF, tumour necrosis factor

Received July 18, 2007. Revised November 5, 2007. Accepted November 8, 2007.


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