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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
著者
前田, 武雄 徳島大学大学院医科学教育部(医学専攻)
キーワード
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
資料タイプ
学位論文
抄録
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.
掲載誌名
Journal of Biological Chemistry
ISSN
1083351X
cat書誌ID
AA1202441X
出版者
American Society for Biochemistry and Molecular Biology
294
15
開始ページ
6017
終了ページ
6026
発行日
2019-02-13
備考
内容要旨・審査要旨・論文本文の公開
本論文は,著者Takeo K. Maedaの学位論文として提出され,学位審査・授与の対象となっている。
This research was originally published in the Journal of Biological Chemistry. Takeo K. Maeda, Daisuke Sugiura, Il-mi Okazaki, Takumi Maruhashi, Taku Okazaki. Atypical motifs in the cytoplasmic region of the inhibitory immune co-receptor LAG-3 inhibit T cell activation. J. Biol. Chem. 2019 Vol.294(15), pp.6017-6026.
権利情報
© 2019 Maeda et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.
EDB ID
出版社版DOI
出版社版URL
フルテキストファイル
言語
eng
著者版フラグ
博士論文全文を含む
文科省報告番号
甲第3319号
学位記番号
甲医第1421号
学位授与年月日
2019-06-27
学位名
博士(医学)
学位授与機関
徳島大学
部局
先端酵素学研究所