title: General control non-derepressible 2 (GCN2) in T cells controls disease progression of autoimmune neuroinflammation.
abstract: Relapsing-remitting multiple sclerosis (MS)(2) is characterized by phases of acute neuroinflammation followed by spontaneous remission. Termination of inflammation is accompanied by an influx of regulatory T cells (Tregs).(3) The molecular mechanisms responsible for directing Tregs into the inflamed CNS tissue, however, are incompletely understood. In an MS mouse model we show that the stress kinase general control non-derepressible 2 (GCN2),(4) expressed in T cells, contributes to the resolution of autoimmune neuroinflammation. Failure to recover from acute inflammation was associated with reduced frequencies of CNS-infiltrating Tregs. GCN2 deficient Tregs displayed impaired migration to a CCL2 gradient. These data suggest an important contribution of the T cell stress response to the resolution of autoimmune neuroinflammation.
authors.affiliation: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address: m.keil@dkfz-heidelberg.de.
authors.forename: Melanie
authors.initials: M
authors.lastname: Keil
authors.affiliation: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address: j.sonner@dkfz-heidelberg.de.
authors.forename: Jana K
authors.initials: JK
authors.lastname: Sonner
authors.affiliation: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Department of Neurology and National Center of Tumor Diseases (NCT), University Hospital Heidelberg, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany. Electronic address: t.lanz@dkfz-heidelberg.de.
authors.forename: Tobias V
authors.initials: TV
authors.lastname: Lanz
authors.affiliation: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address: i.oezen@dkfz-heidelberg.de.
authors.forename: Iris
authors.initials: I
authors.lastname: Oezen
authors.affiliation: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address: t.bunse@dkfz-heidelberg.de.
authors.forename: Theresa
authors.initials: T
authors.lastname: Bunse
authors.affiliation: Department of Neurology, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany. Electronic address: stefan.bittner@unimedizin-mainz.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bittner
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. Electronic address: hannah@ebi.ac.uk.
authors.forename: Hannah V
authors.initials: HV
authors.lastname: Meyer
authors.affiliation: Department of Neurology, University of Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany. Electronic address: sven.meuth@ukmuenster.de.
authors.forename: Sven G
authors.initials: SG
authors.lastname: Meuth
authors.affiliation: Department of Neurology and National Center of Tumor Diseases (NCT), University Hospital Heidelberg, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany; DKTK Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address: w.wick@dkfz-heidelberg.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.affiliation: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Department of Neurology and National Center of Tumor Diseases (NCT), University Hospital Heidelberg, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany. Electronic address: m.platten@dkfz-heidelberg.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Platten
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000166:cytology; D002465:Cell Movement / Q000502:physiology; D016207:Cytokines / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000503:physiopathology*; D042783:Endothelial Cells / Q000502:physiology; D005260:Female; D005434:Flow Cytometry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D010446:Peptide Fragments / Q000633:toxicity; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D018709:Statistics, Nonparametric; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
chemical_list: D017304:Annexin A5; D016207:Cytokines; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: CCL2; Chemokines; Experimental autoimmune encephalomyelitis (EAE); General control non-derepressible 2 (GCN2); Regulatory T cell (T(reg))