| Project/Area Number |
15078201
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | RIKEN (2004-2006)
Chiba University (2003) |
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Principal Investigator |
SAITO Takashi RIKEN, Laboratory for Cell Singaling, Group Director, 免疫シグナル研究グループ, グループディレクター (50205655)
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| Co-Investigator(Kenkyū-buntansha) |
荒瀬 尚 千葉大学, 大学院・医学研究院, 助教授 (10261900)
村上 正晃 大阪大学, 大学院・医学研究科, 助教授 (00250514)
阪口 薫雄 熊本大学, 医学部, 教授 (70192086)
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| Project Period (FY) |
2003 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥159,400,000 (Direct Cost: ¥159,400,000)
Fiscal Year 2006: ¥29,600,000 (Direct Cost: ¥29,600,000)
Fiscal Year 2005: ¥29,600,000 (Direct Cost: ¥29,600,000)
Fiscal Year 2004: ¥28,200,000 (Direct Cost: ¥28,200,000)
Fiscal Year 2003: ¥72,000,000 (Direct Cost: ¥72,000,000)
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| Keywords | Immunology / signal transduction / T cell / immunological synapse / NFκB / IRAK-4 / ADAP / NFκB / T細胞活性化 / ラフト / 自然免疫系 / 獲得免疫系 / シグナルクロストーク / lipid raft / CTLA-4 / 制御性T細胞 / 免疫寛容 / キラーT細胞 / 細胞分裂 / アクチン再構成 / ペア型レセブター / PILR / 高親和性抗体 / GANP / IL-6 / 樹状細胞 |
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| Research Abstract |
We aimed to clarify the mechanism on the acquisition of the information of immune recognition and regulation of immune responses. As the central mechanism of immune surveillance, dendritic cells (DC) first recognize pathogens upon infection, and then innate immunity is activated, which in turn induces antigen-specific recognition and activation of T cells. In this project, we have clarified that IRAK-4, a central regulatory serin/threonine kinase in innate immune signaling, plays also a critical role in T cell activation as the central response in the adaptive immunity. In IRAK-4-deficient mice, proliferation and cytotoxic function of CD8+ T cells were impaired upon LCMV infection. We analyzed whether the impaired response was attributed to the defects in innate response by DCs or T cells by using T cell transfer experiments, and found that T cell activation was impaired in both MHC class I and II-restricted responses. Indeed, we found that not only in vivo T cell responses but also in vitro responses including allogenic responses, super-antigen responses, and responses upon anti-TCR stimulation. By analyzing the defective signaling pathways, particularly NF-AT or NF-κB activation pathways, we found that NF-κB activation was suppressed and impaired phosphorylation of PKCθ appeared to be responsible for the defective NF-κB activation. These results indicate that IRAK-4 plays a critical role in TCR activation signals by directing towards NF-κB activation. We further analyzed the mechanism of IRAK-4-mediated NF-κB specific activation, and found that IRAK-4 associates with ZAP-70 in the over-expression system. IRAK-4 appears to be recruited together with ZAP-70 to the vicinity of TCR upon stimulation, and is involved in activation regulation. Our result that IRAK-4 is important for NF-KB activation in both innate and acquired immunities suggests that NF-κB activation by IRAK-4 has been conserved through phylogenic development.
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