2005 Fiscal Year Final Research Report Summary
Trial of disease specific immunotherapy using antigen-specific T cells and immunoregulatory genes.
| Project/Area Number |
16590980
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
膠原病・アレルギー・感染症内科学
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| Research Institution | Kyoto University |
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Principal Investigator |
USUI Takshi Kyoto University, Faculty of Medicine, Assistant Professor (90362483)
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| Co-Investigator(Kenkyū-buntansha) |
NISHIKOMORI Ryuta Kyoto University, Faculty of Medicine, Assistant Professor (70359800)
WAKATSUKI Yoshio Kyoto University, Faculty of Medicine, Lecturer (40220826)
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| Project Period (FY) |
2004 – 2005
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| Keywords | helper T cell / Th1 / Th2 / T-bet / STAT4 / STAT1 / IFN-gamma |
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| 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.
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Research Products
(4 results)
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[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
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Journal Title
Autoimmunity 39
Pages: 233-41
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[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
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