Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes

Immunity. 2004 Nov;21(5):719-31. doi: 10.1016/j.immuni.2004.09.010.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Differentiation
  • DNA-Binding Proteins / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / therapy
  • Interferon-gamma / genetics
  • Interleukin-12 / pharmacology
  • Mice
  • Oligonucleotides, Antisense / pharmacology
  • RNA, Small Interfering / pharmacology
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin-12
  • STAT1 Transcription Factor
  • STAT4 Transcription Factor
  • T-Box Domain Proteins
  • T-Lymphocytes / cytology*
  • Trans-Activators / genetics
  • Transcription Factors / genetics
  • Transcription Factors / physiology*


  • DNA-Binding Proteins
  • Oligonucleotides, Antisense
  • RNA, Small Interfering
  • Receptors, Interleukin
  • Receptors, Interleukin-12
  • STAT1 Transcription Factor
  • STAT4 Transcription Factor
  • Stat1 protein, mouse
  • Stat4 protein, mouse
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Trans-Activators
  • Transcription Factors
  • Interleukin-12
  • Interferon-gamma