Inhibitory mechanism of T cell function by inhibitory receptors
Project/Area Number |
18H02672
|
Research Category |
Grant-in-Aid for Scientific Research (B)
|
Allocation Type | Single-year Grants |
Section | 一般 |
Review Section |
Basic Section 49070:Immunology-related
|
Research Institution | Institute of Physical and Chemical Research |
Principal Investigator |
Saito Takashi 国立研究開発法人理化学研究所, 生命医科学研究センター, チームリーダー (50205655)
|
Project Period (FY) |
2018-04-01 – 2021-03-31
|
Project Status |
Completed (Fiscal Year 2020)
|
Budget Amount *help |
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2018: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
|
Keywords | T細胞 / 抑制性レセプター / ミクロクラスター / PD-1 / チェックポイント阻害剤 / LAG-3 / TIGIT / 活性化シグナル / T細胞活性化 / TCRミクロクラスター / LAG3 / イメージング解析 / 抑制機能 |
Outline of Final Research Achievements |
T cells are dysfunction in chronic infection and cancer. This dysfunction is induced by inhibitory signals through inhibitory receptors as PD-1. This study analyzed inhibitory mechanism of T cell activation and function by such inhibitory receptor LAG-3. LAG-3 induced cluster formation upon T cell activation which are co-localized with TCR-microclusters. LAG-3-mediated inhibition of T cell activation depends on cytoplasmic region of LAG-3, but the cluster formation did not require the cytoplasmic region. While anti-LAG-3 augmented T cell activation, bi-specific Ab against LAG-3 and PD-1 induced stronger activation. Analysis of inhibitory anti-LAG-3 Abs, it was suggested that inhibitory function of LAG-3 do not require MHC-II association but do need assembly with the TCR complex.
|
Academic Significance and Societal Importance of the Research Achievements |
がんに対するチェックポイント療法が大きく進み、より良い療法が期待されている。PD-1やCTLA-4以外の抑制性受容体の制御によって疲弊T細胞を活性化が示唆されている。その代表の抑制受容体LAG-3を介したT細胞機能の抑制メカニズムを明らかにすることは、PD-1との異同を含めて、学術的に極めて重要であり、実際に臨床で使用するためにLAG-3の機能機作の解明は必須である。また、今回PD-1とLAG-3のbi-specific抗体についても解析したが、実際にこのbi-specific抗体が、現状のPD-1抗体に替わる日は遠くないと思われ、その基本的性状の解析もまた大変意義のあることである。
|
Report
(4 results)
Research Products
(20 results)
-
-
-
[Journal Article] Inhibition of T cell activation and function by the adaptor protein CIN85.2019
Author(s)
Kong Mei S*., Hashimoto-Tane A*., Kawashima Y., Sakuma M., Yokosuka T., Kometani K., Onishi R., Carpino N., Ohara O., Kurosaki T., Phua K.K. and Saito, T.
-
Journal Title
Sci Signal
Volume: 12
Pages: 1609-1625
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
-
-
-
[Journal Article] Reciprocal regulation of STING and TCR signaling by mTORC1 for T-cell activation and function.2019
Author(s)
Imanishi, T., M. Unno, W. Kobayashi, N. Yoneda, S. Matsuda, K. Ikeda, T. Hoshii, A. Hirao, K. Miyake, G. N. Barber, M. Arita, K. J. Ishii, S. Akira, and T, Saito.
-
Journal Title
Life Sci Alliance
Volume: 2
Issue: 1
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
-
-
-
-
-
-
-
-
-
-
-
-
-
-