title: RGC-32 Promotes Th17 Cell Differentiation and Enhances Experimental Autoimmune Encephalomyelitis.
abstract: Th17 cells play a critical role in autoimmune diseases, including multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Response gene to complement (RGC)-32 is a cell cycle regulator and a downstream target of TGF-β that mediates its profibrotic activity. In this study, we report that RGC-32 is preferentially upregulated during Th17 cell differentiation. RGC-32-/-mice have normal Th1, Th2, and regulatory T cell differentiation but show defective Th17 differentiation in vitro. The impaired Th17 differentiation is associated with defects in IFN regulatory factor 4, B cell-activating transcription factor, retinoic acid-related orphan receptor γt, and SMAD2 activation. In vivo, RGC-32-/-mice display an attenuated experimental autoimmune encephalomyelitis phenotype accompanied by decreased CNS inflammation and reduced frequency of IL-17- and GM-CSF-producing CD4+T cells. Collectively, our results identify RGC-32 as a novel regulator of Th17 cell differentiation in vitro and in vivo and suggest that RGC-32 is a potential therapeutic target in multiple sclerosis and other Th17-mediated autoimmune diseases.
authors.affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201; vrus@umaryland.edu.|Research Service, Veteran Affairs Medical Center, Baltimore, MD 21201.
authors.forename: Violeta
authors.initials: V
authors.lastname: Rus
authors.affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201.|Research Service, Veteran Affairs Medical Center, Baltimore, MD 21201.
authors.forename: Vinh
authors.initials: V
authors.lastname: Nguyen
authors.affiliation: Research Service, Veteran Affairs Medical Center, Baltimore, MD 21201.|Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Alexandru
authors.identifier: 0000-0003-2674-3278
authors.initials: A
authors.lastname: Tatomir
authors.affiliation: Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Lees
authors.affiliation: Research Service, Veteran Affairs Medical Center, Baltimore, MD 21201.|Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Armugam P
authors.identifier: 0000-0001-7142-3594
authors.initials: AP
authors.lastname: Mekala
authors.affiliation: Research Service, Veteran Affairs Medical Center, Baltimore, MD 21201.|Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Dallas
authors.initials: D
authors.lastname: Boodhoo
authors.affiliation: Research Service, Veteran Affairs Medical Center, Baltimore, MD 21201.|Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Cosmin A
authors.initials: CA
authors.lastname: Tegla
authors.affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201.|Research Service, Veteran Affairs Medical Center, Baltimore, MD 21201.
authors.forename: Irina G
authors.initials: IG
authors.lastname: Luzina
authors.affiliation: Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Antony
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Cornelia D
authors.initials: CD
authors.lastname: Cudrici
authors.affiliation: Retinal Circuit Development and Genetics Unit, Neurobiology Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Tudor C
authors.initials: TC
authors.lastname: Badea
authors.affiliation: Research Service, Veteran Affairs Medical Center, Baltimore, MD 21201.|Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201.
authors.forename: Horea G
authors.initials: HG
authors.lastname: Rus
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D002490:Central Nervous System / Q000276:immunology / Q000503:physiopathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000276:immunology; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics* / Q000494:pharmacology / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D000099218:Interferon Regulatory Factor-4
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D050835:Interferon Regulatory Factors; D009687:Nuclear Proteins; D018168:Receptors, Retinoic Acid; D000099218:Interferon Regulatory Factor-4; C520017:Rgc-32 protein, mouse