Atypical motifs in the cytoplasmic region of the inhibitory immune co-receptor LAG-3 inhibit T cell activation 15

• Material Type: 博士論文
• ISSN: 1083-351X
• Title: Atypical motifs in the cytoplasmic region of the inhibitory immune co-receptor LAG-3 inhibit T cell activation
• Volume: 294 15
• Author/Editor: Maeda, Takeo K.; Sugiura, Daisuke; Okazaki, Il-mi; Maruhashi, Takumi; Okazaki, Taku
• Author Heading: Maeda, Takeo K.; Sugiura, Daisuke; Okazaki, Il-mi; Maruhashi, Takumi; Okazaki, Taku
• Publication, Distribution, etc.: American Society for Biochemistry and Molecular Biology
• Publication Date: 2019-02-13
• Publication Date (W3CDTF): 2019-02-13
• Alternative Title: 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; Inhibitory mechanisms of LAG-3–dependent T cell suppression
• Periodical title: Journal of Biological Chemistry
• Degree grantor/type: 徳島大学
• Date Granted: 2019-06-27
• Date Granted (W3CDTF): 2019-06-27
• Dissertation Number: 甲第3319号
• Degree Type: 博士（医学）
• Conferring No. (Dissertation): 甲第3319号
• Text Language Code: eng
• Subject Heading: 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
• Target Audience: 一般
• Note (General): 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.
• DOI: info:doi/10.1074/jbc.RA119.007455; https://doi.org/info:doi/10.1074/jbc.RA119.007455
• Persistent ID (NDL): info:ndljp/pid/11458150; https://dl.ndl.go.jp/pid/11458150
• Collection: 障害者向け資料
• Collection (Materials For Handicapped People:1): テキストデータ
• Collection (particular): 国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文; https://dl.ndl.go.jp/collections/A00014
• Acquisition Basis: 博士論文（自動収集）
• Date Accepted (W3CDTF): 2020-03-11T23:38:06+09:00
• Format (IMT): application/pdf
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• Periodical Title (URI): http://repo.lib.tokushima-u.ac.jp/113688
• Data Provider (Database): 国立国会図書館 : 国立国会図書館デジタルコレクション; https://dl.ndl.go.jp