title: Impact of suppressing retinoic acid-related orphan receptor gamma t (ROR)γt in ameliorating central nervous system autoimmunity.
abstract: Multiple sclerosis (MS) is an immune-mediated chronic central nervous system (CNS) disease affecting more than 400 000 people in the United States. Myelin-reactive CD4 T cells play critical roles in the formation of acute inflammatory lesions and disease progression in MS and experimental autoimmune encephalomyelitis (EAE), a well-defined mouse model for MS. Current MS therapies are only partially effective, making it necessary to develop more effective therapies that specifically target pathogenic myelin-specific CD4 T cells for MS treatment. While suppressing T-bet, the key transcription factor in T helper type 1 (Th1) cells, has been demonstrated to be beneficial in prevention and treatment of EAE, the therapeutic potential of retinoic acid-related orphan receptor gamma t (ROR)γt, the key transcription factor for Th17 cells, has not been well-characterized. In this study, we characterized the correlation between RORγt expression and other factors affecting T cell encephalitogenicity and evaluated the therapeutic potential of targeting RORγt by siRNA inhibition of RORγt. Our data showed that RORγt expression correlates with interleukin (IL)-17 production, but not with the encephalitogenicity of myelin-specific CD4 T cells. IL-23, a cytokine that enhances encephalitogenicity, does not enhance RORγt expression significantly. Additionally, granulocyte-macrophage colony-stimulating factor (GM-CSF) levels, which correlate with the encephalitogenicity of different myelin-specific CD4 T cell populations, do not correlate with RORγt. More importantly, inhibiting RORγt expression in myelin-specific CD4 T cells with an siRNA does not reduce disease severity significantly in adoptively transferred EAE. Thus, RORγt is unlikely to be a more effective therapeutic target for ameliorating pathogenicity of encephalitogenic CD4 T cells.
authors.affiliation: Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.forename: R C
authors.initials: RC
authors.lastname: Winger
authors.forename: P W
authors.initials: PW
authors.lastname: Lee
authors.forename: P K
authors.initials: PK
authors.lastname: Nuro-Gyina
authors.forename: A
authors.initials: A
authors.lastname: Minc
authors.forename: M
authors.initials: M
authors.lastname: Larson
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: W
authors.initials: W
authors.lastname: Pei
authors.forename: E
authors.initials: E
authors.lastname: Rieser
authors.forename: M K
authors.initials: MK
authors.lastname: Racke
authors.forename: A E
authors.initials: AE
authors.lastname: Lovett-Racke
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002490:Central Nervous System / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D053759:Interleukin-23 / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology; D009186:Myelin Sheath / Q000276:immunology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference
chemical_list: D053759:Interleukin-23; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: EAE; RORγt; T cell encephalitogenicity; multiple sclerosis; transcription factor