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

• Material Type: 博士論文
• Title: Atypical motifs in the cytoplasmic region of the inhibitory immune co-receptor LAG-3 inhibit T cell activation
• 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
• No. or year of volume/issue: 294 15
• Volume: 294
• Issue: 15
• Pages: 6017-6026
• ISSN (Periodical Title): ISSN : 1083-351X
• Degree grantor/type: 徳島大学
• Date Granted: 2019-06-27
• Dissertation Number: 甲第3319号
• Degree Type: 博士（医学）
• 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.
• Format (IMT): application/pdf
• Source: comment：fulltext; http://repo.lib.tokushima-u.ac.jp/files/public/11/113688/20190830140014521198/k3319_abstract.pdf; http://repo.lib.tokushima-u.ac.jp/files/public/11/113688/2019083014001587721/k3319_review.pdf; http://repo.lib.tokushima-u.ac.jp/files/public/11/113688/20190830140015443298/k3319_fulltext.pdf
• Access Restrictions: インターネット公開
• Rights (production): © 2019 Maeda et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.
• Related Material (DOI): 10.1074/jbc.RA119.007455
• Periodical Title (NCID): AA1202441X; https://ci.nii.ac.jp/ncid/AA1202441X
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 徳島大学 : 徳島大学機関リポジトリ