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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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EID
356654
EOID
956577
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0
LastModified
2019年8月19日(月) 11:32:05
Operator
岡崎 拓
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Owner
岡崎 拓
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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
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著者 必須
  1. (英) Maeda K. Takeo
    役割 任意
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    学籍番号 推奨
  2. 杉浦 大祐
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  3. 岡崎 一美
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    貢献度 任意
    学籍番号 推奨
  4. 丸橋 拓海
    役割 任意
    貢献度 任意
    学籍番号 推奨
  5. 岡崎 拓
    役割 任意
    貢献度 任意
    学籍番号 推奨
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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(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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誌名 必須 The Journal of Biological Chemistry([The American Society for Biochemistry and Molecular Biology])
(pISSN: 0021-9258, eISSN: 1083-351X)
ISSN 任意 1083-351X
ISSN: 0021-9258 (pISSN: 0021-9258, eISSN: 1083-351X)
Title: The Journal of biological chemistry
Title(ISO): J Biol Chem
Publisher: American Society for Biochemistry and Molecular Biology
 (NLM Catalog  (Scopus  (CrossRef (Scopus information is found. [need login])
必須 294
必須 15
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)
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  1. (英) Article.ELocationID: 10.1074/jbc.RA119.007455

  2. (英) Article.PublicationTypeList.PublicationType: Journal Article

  3. (英) KeywordList.Keyword: LAG-3

  4. (英) KeywordList.Keyword: T cell

  5. (英) KeywordList.Keyword: T cell receptor (TCR)

  6. (英) KeywordList.Keyword: co-receptor

  7. (英) KeywordList.Keyword: cytokine induction

  8. (英) KeywordList.Keyword: immune checkpoint

  9. (英) KeywordList.Keyword: immunology

  10. (英) KeywordList.Keyword: immunotherapy

  11. (英) KeywordList.Keyword: inhibition mechanism

  12. (英) KeywordList.Keyword: monoclonal antibody