TY - JOUR
T1 - Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes
AU - Lovett-Racke, Amy E.
AU - Rocchini, Anne E.
AU - Choy, Judy
AU - Northrop, Sara C.
AU - Hussain, Rehana Z.
AU - Ratts, Robert B.
AU - Sikder, Devanjan
AU - Racke, Michael K.
N1 - Funding Information:
We thank Dr. Thomas Kodadek for helping establish the chromatin immunoprecipitation assay in our laboratory. We also thank Dr. Nitin Karandikar for assisting us with the intracellular staining and flow cytometry. This study was supported by grants from the Yellow Rose Foundation, Once Upon A Time…, and the National Institutes of Health (R01 NS037513 and K24 NS044250).
PY - 2004/11
Y1 - 2004/11
N2 - 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, IFNγ 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 IFNγ and STAT1 promoters, but did not regulate the IL-12/STAT4 pathway. Since T-bet regulates IFNγ production in CD4+ T cells, but to a lesser extent in most other IFNγ-producing cells, T-bet may be a target for therapeutics for Th1-mediated diseases.
AB - 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, IFNγ 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 IFNγ and STAT1 promoters, but did not regulate the IL-12/STAT4 pathway. Since T-bet regulates IFNγ production in CD4+ T cells, but to a lesser extent in most other IFNγ-producing cells, T-bet may be a target for therapeutics for Th1-mediated diseases.
UR - https://www.scopus.com/pages/publications/8444226727
U2 - 10.1016/j.immuni.2004.09.010
DO - 10.1016/j.immuni.2004.09.010
M3 - Article
C2 - 15539157
AN - SCOPUS:8444226727
SN - 1074-7613
VL - 21
SP - 719
EP - 731
JO - Immunity
JF - Immunity
IS - 5
ER -