title: RORγt-specific transcriptional interactomic inhibition suppresses autoimmunity associated with TH17 cells.
abstract: The nuclear hormone receptor retinoic acid-related orphan receptor gamma t (RORγt) is a transcription factor (TF) specific to TH17 cells that produce interleukin (IL)-17 and have been implicated in a wide range of autoimmunity. Here, we developed a novel therapeutic strategy to modulate the functions of RORγt using cell-transducible form of transcription modulation domain of RORγt (tRORγt-TMD), which can be delivered effectively into the nucleus of cells and into the central nerve system (CNS). tRORγt-TMD specifically inhibited TH17-related cytokines induced by RORγt, thereby suppressing the differentiation of naïve T cells into TH17, but not into TH1, TH2, or Treg cells. tRORγt-TMD injected into experimental autoimmune encephalomyelitis (EAE) animal model can be delivered effectively in the splenic CD4(+) T cells and spinal cord-infiltrating CD4(+) T cells, and suppress the functions of TH17 cells. The clinical severity and incidence of EAE were ameliorated by tRORγt-TMD in preventive and therapeutic manner, and significant reduction of both infiltrating CD4(+) IL-17(+) T cells and inflammatory cells into the CNS was observed. As a result, the number of spinal cord demyelination was also reduced after tRORγt-TMD treatment. With the same proof of concept, tTbet-TMD specifically blocking TH1 differentiation improved the clinical incidence of rheumatoid arthritis (RA). Therefore, tRORγt-TMD and tTbet-TMD can be novel therapeutic reagents with the natural specificity for the treatment of inflammatory diseases associated with TH17 or TH1. This strategy can be applied to treat various diseases where a specific transcription factor has a key role in pathogenesis.
authors.affiliation: Department of Biotechnology, College of Life Science and Biotechnology, Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Republic of Korea;
authors.forename: Tae-Yoon
authors.initials: TY
authors.lastname: Park
authors.affiliation: Department of Biotechnology, College of Life Science and Biotechnology, Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Republic of Korea;
authors.forename: Sung-Dong
authors.initials: SD
authors.lastname: Park
authors.affiliation: Department of Biotechnology, College of Life Science and Biotechnology, Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Republic of Korea;
authors.forename: Jen-Young
authors.initials: JY
authors.lastname: Cho
authors.affiliation: Department of Biotechnology, College of Life Science and Biotechnology, Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Republic of Korea;
authors.forename: Jae-Seung
authors.initials: JS
authors.lastname: Moon
authors.affiliation: Department of Biotechnology, College of Life Science and Biotechnology, Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Republic of Korea;
authors.forename: Na-Yeon
authors.initials: NY
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Republic of Korea;
authors.forename: Kyungsoo
authors.initials: K
authors.lastname: Park
authors.affiliation: Department of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Republic of Korea;
authors.forename: Rho Hyun
authors.initials: RH
authors.lastname: Seong
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Institute for Immunology and Immunological Disease, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea;
authors.forename: Sang-Won
authors.initials: SW
authors.lastname: Lee
authors.affiliation: Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; and.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Morio
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Alfred L M
authors.initials: AL
authors.lastname: Bothwell
authors.affiliation: Department of Biotechnology, College of Life Science and Biotechnology, Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Republic of Korea; sjrlee@yonsei.ac.kr.
authors.forename: Sang-Kyou
authors.initials: SK
authors.lastname: Lee
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002467:Cell Nucleus / Q000276:immunology* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology
chemical_list: D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human
keywords: RORγt; TH17; TMD; autoimmunity; transcription factor