title: Gatekeeper role of brain antigen-presenting CD11c+ cells in neuroinflammation.
abstract: Multiple sclerosis is the most frequent chronic inflammatory disease of the CNS. The entry and survival of pathogenic T cells in the CNS are crucial for the initiation and persistence of autoimmune neuroinflammation. In this respect, contradictory evidence exists on the role of the most potent type of antigen-presenting cells, dendritic cells. Applying intravital two-photon microscopy, we demonstrate the gatekeeper function of CNS professional antigen-presenting CD11c(+) cells, which preferentially interact with Th17 cells. IL-17 expression correlates with expression of GM-CSF by T cells and with accumulation of CNS CD11c(+) cells. These CD11c(+) cells are organized in perivascular clusters, targeted by T cells, and strongly express the inflammatory chemokines Ccl5, Cxcl9, and Cxcl10. Our findings demonstrate a fundamental role of CNS CD11c(+) cells in the attraction of pathogenic T cells into and their survival within the CNS. Depletion of CD11c(+) cells markedly reduced disease severity due to impaired enrichment of pathogenic T cells within the CNS.
authors.affiliation: Department of Neurology, Focus Program Translational Neurosciences (FTN), Research Center for Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn²) University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Paterka
authors.affiliation: Department of Neurology, Focus Program Translational Neurosciences (FTN), Research Center for Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn²) University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Siffrin
authors.affiliation: Molecular Neurology, Max Delbrück Center for Molecular Medicine Berlin-Buch, Berlin, Germany.
authors.forename: Jan O
authors.initials: JO
authors.lastname: Voss
authors.affiliation: Molecular Neurology, Max Delbrück Center for Molecular Medicine Berlin-Buch, Berlin, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Werr
authors.affiliation: Department of Neurology, Focus Program Translational Neurosciences (FTN), Research Center for Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn²) University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Nicola
authors.initials: N
authors.lastname: Hoppmann
authors.affiliation: Department of Neurology, Focus Program Translational Neurosciences (FTN), Research Center for Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn²) University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Gollan
authors.affiliation: Department of Neurology, Focus Program Translational Neurosciences (FTN), Research Center for Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn²) University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Belikan
authors.affiliation: Institute for Molecular Medicine, Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Bruttger
authors.affiliation: Department of Neurology, Focus Program Translational Neurosciences (FTN), Research Center for Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn²) University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Birkenstock
authors.affiliation: Department of Immunology Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Steffen
authors.initials: S
authors.lastname: Jung
authors.affiliation: Howard Hughes Medical Institute Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Enric
authors.initials: E
authors.lastname: Esplugues
authors.affiliation: Institute for Molecular Medicine, Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Nir
authors.initials: N
authors.lastname: Yogev
authors.affiliation: Howard Hughes Medical Institute Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.affiliation: Institute for Immunology, Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bopp
authors.affiliation: Department of Neurology, Focus Program Translational Neurosciences (FTN), Research Center for Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn²) University Medical Center of the Johannes Gutenberg University, Mainz, Germany frauke.zipp@unimedizin-mainz.de.
authors.forename: Frauke
authors.initials: F
authors.lastname: Zipp
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000737:chemistry / Q000502:physiology*; D001921:Brain / Q000276:immunology / Q000473:pathology*; D039521:CD11c Antigen / Q000032:analysis*; D002465:Cell Movement; D003713:Dendritic Cells / Q000737:chemistry / Q000502:physiology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D058504:Th17 Cells / Q000502:physiology
chemical_list: D039521:CD11c Antigen; D020381:Interleukin-17; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: EAE/MS; Th17; chemokines; dendritic cells; two‐photon microscopy