| Project/Area Number |
09044332
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| Research Category |
Grant-in-Aid for international Scientific Research
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| Allocation Type | Single-year Grants |
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| Section | Joint Research |
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| Research Field |
Immunology
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| Research Institution | Keio University |
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Principal Investigator |
KOYASU Shigeo Keio University, School of Medicine, Professor, 医学部, 教授 (90153684)
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| Co-Investigator(Kenkyū-buntansha) |
REINHERZ Ellis L Harvard Medical School, Professor, 医学部ダナファイバー癌研究所, 教授
MATSUDA Satoshi Keio University, School of Medicine, Instructor, 医学部, 助手 (00286444)
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| Project Period (FY) |
1997 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1998: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1997: ¥600,000 (Direct Cost: ¥600,000)
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| Keywords | tolerance / cyclosporin A / ITAM / T cell receptor / MAP kinase superfamily / ITAM / チロシンキナーゼ / キメラ分子 / カルシウムイオン |
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| Research Abstract |
1)Signals generated by TCR stimulation alone is not sufficient to activate IL2 gene and thus induces anergy in resting lymphocytes. We found that TCR stimulation alone induces activation of MAPK/ERK but not SAPK/JNK and p38/CSBP.In constrast, when T cells were stimulated through both TCR and CD28 to produce IL-2, all three MAPK superfamily members were activated.
2)SAPK/JNK arid p38/CSBP pathways form redundant pathways and MAPK/ERK pathway synergistically function with SAPK/JNK and p38/CSBP pathways in activation of IL2 gene.
3)Activation of SAPK/JNK and p38/CSBP pathways but not MAPK/ERK pathway is sensitive to cyclosporin A.Since activation of SAPK/JNK and p38/CSBP pathways by osmotic shock is not inhibited by cyclosporin A, it is likely that there is a cyclosporin A sensitive step between TCR/CD28 and activation of SAPK/JNK and p38/CSBP pathways.
4)Functional analysis of the immunoreceptor tyrosine-based activation motif (ITAM) derived from the membrane proximal ITAM of CD3zeta demonstrates that mutations at either the tyrosine or leucine residues in the N-terminal YxxL segment of the ITAM abolish all signal transduction functions of this ITAM.In contrast, mutations at the tyrosine or leucine residues in the C-terminal YxxL segment abrogate signals for IL-2 production but do not prevent calcium mobilization. Crosslinking of chimeric receptors containing a C-terminal YxxL leucine mutation induces tyrosine phosphorylation of ZAP7O but without stable binding to the phosphorylated ITAM.These results indicate that the two YxxL segments in an ITAM are functionally distinct and that both are essential for ZAP7O binding and IL-2 production.
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