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.

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@article{LovettRacke2004SilencingTD, title={Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes.}, author={Amy E. Lovett-Racke and Anne E Rocchini and Judy Choy and Sara C Northrop and Rehana Z. Hussain and Robert B Ratts and Devanjan Sikder and Michael Karl Racke}, journal={Immunity}, year={2004}, volume={21 5}, pages={719-31} }