Gatekeeper role of brain antigen‐presenting CD11c+ cells in neuroinflammation |
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Authors: | Nicola Hoppmann René Gollan Patrick Belikan Julia Bruttger Jérôme Birkenstock Steffen Jung Enric Esplugues Nir Yogev Richard A Flavell Tobias Bopp Frauke Zipp |
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Affiliation: | 1. 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;2. Institute for Molecular Medicine, Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany;3. Department of Immunology, Weizmann Institute of Science, Rehovot, Israel;4. Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA;5. Institute for Immunology, Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg University, Mainz, Germany |
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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. |
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Keywords: | chemokines dendritic cells EAE/MS Th17 two‐photon microscopy |
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