2000 Fiscal Year Final Research Report Summary
Signal transduction regulating the differentiation and the function of T cells
| Project/Area Number |
10307008
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| Research Category |
Grant-in-Aid for Scientific Research (A).
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Immunology
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| Research Institution | Chiba University |
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Principal Investigator |
SAITO Takashi Chiba University, Graduate School of Medicine, Proffesor, 大学院・医学研究科, 教授 (50205655)
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| Co-Investigator(Kenkyū-buntansha) |
YAMASAKI Sho Chiba University, Graduate School of Medicine, Assistant, 大学院・医学研究科, 助手 (40312946)
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| Project Period (FY) |
1998 – 2000
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| Keywords | TCR signal / pre T cell receptor / RIT / Knockout mouse / E-box / Gab-2 / CTLA-4 / CAST |
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| Research Abstract |
The mechanism of T cell activation and development has been analyzed from the point of view of signaling. The TCR complex is composed of two signaling modules and one is represented by CD3ε. To analyze CD3ε-containing module, we isolated CD3ε-binding protein CAST.CAST binds to the membrane proximal region of CD3ε and mediates activation signal for NFAT activation and IL-2 signaling. We are continuing the analysis of CAST by producing knockout mice. We analyzed regulatory mechanism of TCR signaling by analyzing negative regulation downstream of TCR by Gab-2 and through co-stimulation receptor CTLA-4. Both negative regulators play roles as feedback regulators since these molecules are induced by TCR activation. Gab-2 suppresses TCR by recruitment of SHP-2 and induces dephosphorylation of CD3ζ. We identified a unique regulatory mechanism to induce cell surface expression and endocytosis of CTLA-4 through accumulation and secretion of C TLA-4-containing lysosomes.
We demonstrated by using CD3ζ-deficient mice that positive and negative selection occurs according to the strength of TCR signal. We also showed the same mechanism could be applied for CD4/CD8 commitment. We succeeded to identify a cDNA clone RIT that encodes molecule specific for pTα-expressing cells by subtraction library. RIT disappeared similar to pTα upon stimulation of pre-TCR in pre-T cells. We analyzed the promoter of pTα gene and identified a tandem E-box responsible for pTα transcription. This E-box plays a more important role than similar E-box in pTα enhancer region. We identified the responsible E-box binding helix-loop-helix factors as HEB and E2A.
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