title: Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes.
abstract: As a means of developing therapies that target the pathogenic T cells in multiple sclerosis (MS) without compromising the immune system or eliciting systemic side effects, we investigated the use of T-bet-specific antisense oligonucleotides and small interfering RNAs (siRNA) to silence T-bet expression in autoreactive encephalitogenic T cells and evaluated the biological consequences of this suppression in experimental autoimmune encephalomyelitis, a model for MS. The T-bet-specific AS oligonucleotide and siRNA suppressed T-bet expression, IFNgamma production, and STAT1 levels during antigen-specific T cell differentiation. In vitro suppression of T-bet during differentiation of myelin-specific T cells and in vivo administration of a T-bet-specific antisense oligonucleotide or siRNA inhibited disease. T-bet was shown to bind the IFNgamma and STAT1 promoters, but did not regulate the IL-12/STAT4 pathway. Since T-bet regulates IFNgamma production in CD4(+) T cells, but to a lesser extent in most other IFNgamma-producing cells, T-bet may be a target for therapeutics for Th1-mediated diseases.
authors.affiliation: Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390 USA. amy.lovett-racke@utsouthwestern.edu
authors.forename: Amy E
authors.initials: AE
authors.lastname: Lovett-Racke
authors.forename: Anne E
authors.initials: AE
authors.lastname: Rocchini
authors.forename: Judy
authors.initials: J
authors.lastname: Choy
authors.forename: Sara C
authors.initials: SC
authors.lastname: Northrop
authors.forename: Rehana Z
authors.initials: RZ
authors.lastname: Hussain
authors.forename: Robert B
authors.initials: RB
authors.lastname: Ratts
authors.forename: Devanjan
authors.initials: D
authors.lastname: Sikder
authors.forename: Michael K
authors.initials: MK
authors.lastname: Racke
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000628:therapy; D007371:Interferon-gamma / Q000235:genetics; D018664:Interleukin-12 / Q000494:pharmacology; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D018123:Receptors, Interleukin / Q000235:genetics; D053707:Receptors, Interleukin-12; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; D020825:T-Box Domain Proteins; D013601:T-Lymphocytes / Q000166:cytology*; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D000098815:T-bet Transcription Factor
chemical_list: D004268:DNA-Binding Proteins; D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; C494080:Stat1 protein, mouse; C494091:Stat4 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D018664:Interleukin-12; D007371:Interferon-gamma