رسالة جامعية
Atypical motifs in the cytoplasmic region of the inhibitory immune co-receptor LAG-3 inhibit T cell activation
| العنوان: | Atypical motifs in the cytoplasmic region of the inhibitory immune co-receptor LAG-3 inhibit T cell activation 抑制性免疫補助受容体LAG-3は細胞質領域に有する非定型モチーフを介してT細胞の活性化を抑制する |
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| المؤلفون: | Maeda, Takeo K., Sugiura, Daisuke, Okazaki, Il-mi, Maruhashi, Takumi, Okazaki, Taku, Maeda, Takeo K., Sugiura, Daisuke, Okazaki, Il-mi, Maruhashi, Takumi, Okazaki, Taku |
| المصدر: | Journal of Biological Chemistry. 294(15) |
| بيانات النشر: | American Society for Biochemistry and Molecular Biology, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | T細胞抗原受容体, 免疫補助受容体, 抑制機構, モノクローナル抗体, LAG-3 |
| نوع الوثيقة: | 博士論文 |
| اللغة: | English |
| تدمد: | 1083-351X |
| ملاحظات: | T cell activation is tightly regulated by both stimulatory and inhibitory co-receptors and has been a focus in the development of interventions for managing cancer or autoimmune diseases. Targeting the inhibitory co-receptors programmed cell death 1 (PD-1) and cytotoxic T lymphocyte–associated protein 4 (CTLA-4) has successfully eradicated tumors but induced immune-related adverse events in humans and mice. The beneficial and adverse effects of targeting these co-receptors highlight their importance in cancer immunity and also autoimmunity. Although the therapeutic potencies of other inhibitory co-receptors are under extensive investigation, their inhibitory mechanisms and their functional differences are not well understood. Here we analyzed the inhibitory mechanisms of lymphocyte activation gene-3 (LAG-3), another inhibitory co-receptor, by using an in vitro T cell activation system and a high-affinity anti-LAG-3 antibody that strongly interferes with the binding of LAG-3 to its ligand. We found that the expression level of LAG-3 strongly correlates with the inhibitory function of LAG-3, suggesting that LAG-3 functions as a rheostat rather than as a breaker of T cell activation. By evaluating the inhibitory capacities of various LAG-3 variants relative to their expression levels, we found that LAG-3 transduces two independent inhibitory signals through an FXXL motif in the membrane-proximal region and the C-terminal EX repeat. These motifs have not been reported previously for inhibitory co-receptors, suggesting that LAG-3 inhibits T cell activation through a nonredundant inhibitory mechanisms along with the other inhibitory co-receptors. Our findings provide a rationale for combinatorial targeting of LAG-3 and the other inhibitory co-receptors to improve cancer immunotherapy. |
| رقم الانضمام: | edsdlc.I002879567.00 |
| قاعدة البيانات: | National Diet Library Digital Collections - 国立国会図書館デジタルコレクション |
Full Text Finder | تدمد: | 1083351X |
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