著作: Maeda K. Takeo/[杉浦 大祐]/[岡崎 一美]/[丸橋 拓海]/[岡崎 拓]/Atypical motifs in the cytoplasmic region of the inhibitory immune co-receptor LAG-3 inhibit T cell activation./[The Journal of Biological Chemistry]
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削除する| 種別 | 必須 | 学術論文(審査論文) | |||
|---|---|---|---|---|---|
| 言語 | 必須 | 英語 | |||
| 招待 | 推奨 | ||||
| 審査 | 推奨 | ||||
| カテゴリ | 推奨 | ||||
| 共著種別 | 推奨 | ||||
| 学究種別 | 推奨 | ||||
| 組織 | 推奨 | ||||
| 著者 | 必須 | ||||
| 題名 | 必須 |
(英) Atypical motifs in the cytoplasmic region of the inhibitory immune co-receptor LAG-3 inhibit T cell activation. |
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| 副題 | 任意 | ||||
| 要約 | 任意 |
(英) 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 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 FL motif in the membrane-proximal region and the C-terminal E 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. |
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| キーワード | 推奨 | ||||
| 発行所 | 推奨 | ||||
| 誌名 | 必須 |
The Journal of Biological Chemistry([The American Society for Biochemistry and Molecular Biology])
(pISSN: 0021-9258, eISSN: 1083-351X)
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| 巻 | 必須 | 294 | |||
| 号 | 必須 | 15 | |||
| 頁 | 必須 | 6017 6026 | |||
| 都市 | 任意 | ||||
| 年月日 | 必須 | 2019年 2月 13日 | |||
| URL | 任意 | ||||
| DOI | 任意 | 10.1074/jbc.RA119.007455 (→Scopusで検索) | |||
| PMID | 任意 | 30760527 (→Scopusで検索) | |||
| NAID | 任意 | ||||
| WOS | 任意 | ||||
| Scopus | 任意 | ||||
| 評価値 | 任意 | ||||
| 被引用数 | 任意 | ||||
| 指導教員 | 推奨 | ||||
| 備考 | 任意 |
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