1995 Fiscal Year Final Research Report Summary
Mechanism of signal transduction through activation motifs of the T cell receptor complex
| Project/Area Number |
06454215
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Immunology
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| Research Institution | Chiba University |
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Principal Investigator |
SAITO Takashi Chiba Univ.・Sch.of Med.Professor, 医学部, 教授 (50205655)
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| Co-Investigator(Kenkyū-buntansha) |
MIYATAKE Shoichiro Chiba Univ.・Sch.of Med.Research Associate, 医学部, 助手 (30239420)
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| Project Period (FY) |
1994 – 1995
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| Keywords | T cell receptor / CD3 signal motif / CD3 binding molecule / T cell development / cell growth inhibition / topoisomerase II / knock out mice / signal transduction |
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| Research Abstract |
The mechanism of signal transduction through the TCR-CD3 complex and the regulation of T cell development and cell growth by TCR signals were analyzed. We found two distinct signaling modules within the TCR-CD3 complex ; one through CD3zeta and the other through other CD3 molecules. The analysis of mice containing zeta lacking ITAM demonstrated that the signal through the zeta chain is important for the development of immature thymocytes. We have identified the molecules important for pathways through both signal modules. We identified 90kd molecule the phosphorylation of which was TCR signal-specific and depended on the structure of the zeta chain. For the other signaling module, we cloned two new CD3epsilon-binding molecules. One of them was topoisomerase IIbeta. We showed that CD3epsilon and zeta exist in the nuclear fraction and associate with topoIIbeta. To elucidate functional consequence of TCR signal, the regulation of growth inhibition and T cell selection by TCR signal were analyzed. TCR activation induced G1 arrest in growing T cell clones mainly by reducing the expression of cyclin D3. We found that the unresponsiveness to IL-2 was induced by reducing the Jak3 expression upon TCR activation. To elucidate regulation of T cell selection by TCR signal, TCR-transgenic mice bearing a low level of the surface TCR expression was created. The analysis showed that the positive-negative selection of thymocytes was regulated by the TCR expression level and the signal through the TCR complex.
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