2022 Fiscal Year Final Research Report
Signalosome formation and functions of the immune-checkpoint receptor TIGIT regulated by the height of its ectodomain.
| Project/Area Number |
19K22545
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 49:Pathology, infection/immunology, and related fields
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| Research Institution | Tokyo Medical University |
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Principal Investigator |
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| Project Period (FY) |
2019-06-28 – 2023-03-31
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| Keywords | T細胞シグナル / 腫瘍免疫 / 分子イメージング / 免疫シナプス / 免疫チェックポイント / 副刺激受容体 / シグナロソーム / TIGIT |
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| Outline of Final Research Achievements |
Through molecular imaging analysis of the third checkpoint molecule “TIGIT”, we clarified that the height of the immune receptor determines the distribution of the receptors on cell surface and controls the signal unit "signalosome" responsible for the activation of immune cells. In particular, TIGIT competes with the same inhibitory receptor CD96 for binding to the ligand CD155, but they function as independent signalosomes. The result here is a new concept that structural differences directly control biological outputs. In addition, by utilizing the difference in height between molecules, it has become possible to create a methodology that makes immune checkpoint molecules function in a cooperative or competitive manner.
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| Free Research Field |
免疫学
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| Academic Significance and Societal Importance of the Research Achievements |
免疫チェックポイント療法はがんの第四の標準療法としての地位を確立するに至ったが、作用機序に関する知見は非常に乏しい。一方がん免疫の主役であるT細胞においても、TCRと副刺激受容体がどのようにがん抗原の認識やエフェクター細胞への分化誘導を制御しているのか明確に説明できていない。免疫シナプスの固定概念を破った、受容体の高さがその分子の細胞表面局在とクラスター形成さらには機能に直結すること、シグナル伝達の解釈には免疫シナプスとは異なる時間と空間の因子が不可欠であるという新たな概念の提唱し、治療的への応用の観点からも社会性が高い。
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