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2005 Fiscal Year Final Research Report Summary

Trial of disease specific immunotherapy using antigen-specific T cells and immunoregulatory genes.

Research Project

Project/Area Number 16590980
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 膠原病・アレルギー・感染症内科学
Research InstitutionKyoto University

Principal Investigator

USUI Takshi  Kyoto University, Faculty of Medicine, Assistant Professor (90362483)

Co-Investigator(Kenkyū-buntansha) NISHIKOMORI Ryuta  Kyoto University, Faculty of Medicine, Assistant Professor (70359800)
WAKATSUKI Yoshio  Kyoto University, Faculty of Medicine, Lecturer (40220826)
Project Period (FY) 2004 – 2005
Keywordshelper T cell / Th1 / Th2 / T-bet / STAT4 / STAT1 / IFN-gamma
Research Abstract

The aim of this re-search is to establish disease-specific immunotherapy using antigen-specific T cells and immunoregulatory genes. To perform this, it is very important to know what is the critical factor for helper T cells to work as regulatory cells. Therefore, we investigate the molecular mechanism of helper T cell development in the context of Th1 and Th2 cells. T helper type 1 (Th1) development is facilitated by interrelated changes in key intracellular factors, particularly signal transducer and activator of transcription (STAT) 4, T-bet, and GATA-3. Here we show that CD4+ cells from T-bet -/- mice are skewed toward Th2 differentiation by high endogenous GATA-3 levels but exhibit virtually normal Th1 differentiation provided that GATA-3 levels are regulated at an early stage by anti-interleukin (IL)-4 blockade of IL-4 receptor (R) signaling. In addition, under these conditions, Th1 cells from T-bet -/- mice manifest IFNG promoter accessibility as detected by histone acetylation and deoxyribonuclease I hypersensitivity. In related studies, we show that the negative effect of GATA-3 on Th1 differentiation in T-bet -/- cells arises from its ability to suppress STAT4 levels, because if this is prevented by a STAT4-expressing retrovirus, normal Th1 differentiation is observed Finally, we show that retroviral T-bet expression in developing and established Th2 cells leads to down-regulation of GATA-3 levels. These findings lead to a model of T cell differentiation that holds that naive T cells tend toward Th2 differentiation through induction of GATA-3 and subsequent down-regulation of STAT4/1L-12Rβ2 chain unless GATA-3 levels or function is regulated by T-bet Thus, the principal function of T-bet in developing Th1 cells is to negatively regulate GATA-3 rather than to positively regulate the IFNG gene.

  • Research Products

    (4 results)

All 2006

All Journal Article (4 results) (of which Peer Reviewed: 2 results)

  • [Journal Article] Anti-aminoacyl-tRNA synthetase antibodies in clinical course prediction of interstitial lung disease complicated with idiopathic inflammatory myopathies2006

    • Author(s)
      Yoshifuji H, Fujii T, Kobayashi S, Imura Y, Fujita Y, Kawabata D, Usui T, Tanaka M, Nagai S, Umehara H, Mimori T
    • Journal Title

      Autoimmunity 39

      Pages: 233-41

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription2006

    • Author(s)
      Usui T, Preiss JC, Kanno Y, Yao ZJ, Bream JH, O'Shea JJ, Strober W.
    • Journal Title

      J Exp Med 203

      Pages: 755-66

    • Description
      「研究成果報告書概要(和文)」より
    • Peer Reviewed
  • [Journal Article] Anti-aminoacyl-tRNA synthetase antibodies in clinical course prediction of interstitial lung disease complicated with idiopathic inflammatory myopathies2006

    • Author(s)
      Yoshifuji H, Fujii T, Kobayashi S, Imura Y, Fujita Y, Kawabata D, Usui T, Tanaka M, Nagai S, Umehara H, Mimori T.
    • Journal Title

      Autoimmunity 39(3)

      Pages: 233-41

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription2006

    • Author(s)
      Usui T, Preiss JC, Kanno Y, Yao ZJ, Bream JH, O'Shea JJ, Strober W.
    • Journal Title

      J Exp Med. 203(3)

      Pages: 755-66

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2011-06-18  

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