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

• Published in: Brain (London, England : 1878) England : 1878), 2008-03, Vol.131 (3), p.785-799
• Main Authors: Ifergan, Igal, Kébir, Hania, Bernard, Monique, Wosik, Karolina, Dodelet-Devillers, Aurore, Cayrol, Romain, Arbour, Nathalie, Prat, Alexandre
• Format: Article
• Language: English
• Subjects: Adult; Antigen Presentation - immunology; Blood-Brain Barrier - immunology; blood–brain barrier; CD4-Positive T-Lymphocytes - immunology; Cell Differentiation - immunology; Cell Movement - immunology; Cells, Cultured; Chemokines - biosynthesis; CNS; dendritic cells; Dendritic Cells - immunology; Endothelium - immunology; Humans; IL-17; Interferon-gamma - immunology; Interleukin-17 - biosynthesis; Lipopolysaccharide Receptors - analysis; Lymphocyte Culture Test, Mixed; Middle Aged; Monocytes - cytology; Monocytes - immunology; multiple sclerosis; Multiple Sclerosis - immunology; Phagocytosis - immunology; Phenotype; Tumor Necrosis Factor-alpha - immunology
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awm295

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-γ-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.