The blood-brain barrier induces differentiation of migrating monocytes into Th17-polarizing dendritic cells.
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-beta and granulocyte-macrophage colony-stimulating factor. We also demonstrate that these dendritic cells secrete interleukin-12p70, transforming growth factor-beta 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-beta and granulocyte-macrophage colony-stimulating factor.
D000328:Adult; D017951:Antigen Presentation / Q000276:immunology; D001812:Blood-Brain Barrier / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology*; D004727:Endothelium / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis; D018950:Lipopolysaccharide Receptors / Q000032:analysis; D007959:Lymphocyte Culture Test, Mixed; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D009103:Multiple Sclerosis / Q000276:immunology*; D010587:Phagocytosis / Q000276:immunology; D010641:Phenotype; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D018925:Chemokines; D020381:Interleukin-17; D018950:Lipopolysaccharide Receptors; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma