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タイトル別表記
グルココルチコイドはT細胞上のPD-1の発現量を増加することによりPD-1による抑制効果を高める
Glucocorticoids strengthen PD-1 effects
著者
前田, 菜摘 徳島大学大学院医科学教育部(医学専攻)
丸橋, 拓海 Tokushima University|The University of Tokyo KAKEN研究者をさがす
杉浦, 大祐 Tokushima University|The University of Tokyo KAKEN研究者をさがす
Shimizu, Kenji Tokushima University|The University of Tokyo
岡崎, 一美 Tokushima University|The University of Tokyo KAKEN研究者をさがす
岡崎, 拓 Tokushima University|The University of Tokyo KAKEN研究者をさがす
キーワード
immunology
immunosuppression
T cell
T cell receptor
gene expression
glucocorticoid
cytokine induction
PD-1
co-receptor
immune-checkpoint
資料タイプ
学位論文
抄録
The inhibitory co-receptor programmed cell death 1 (PD-1, Pdcd1) plays critical roles in the regulation of autoimmunity, anti-cancer immunity, and immunity against infections. Immunotherapies targeting PD-1 have revolutionized cancer management and instigated various trials of improved cancer immunotherapies. Moreover, extensive trials are underway to potentiate PD-1 function in order to suppress harmful immune responses. Here, we found that both natural and synthetic glucocorticoids (GCs) up-regulate PD-1 on T cells without altering the expression levels of other co-receptors and cell-surface molecules. The GC-induced up-regulation of PD-1 depended on the transactivation of PD-1 transcription mediated through the glucocorticoid receptor (GR). We further found that a GC response element (GRE) 2525 bp upstream from the transcription start site of Pdcd1 is responsible for GC-mediated transactivation. We also observed that in vivo administration of GCs significantly up-regulates PD-1 expression on tumor-infiltrating T cells. By analyzing T cells differing in PD-1 expression, we directly demonstrated that the amount of PD-1 on the cell surface correlates with its inhibitory effect. Accordingly, GCs potentiated the capacity of PD-1 to inhibit T cell activation, suggesting that this PD-1-mediated inhibition contributes, at least in part, to the anti-inflammatory and immunosuppressive effects of GCs. In light of the critical roles of PD-1 in the regulation of autoimmunity regulation, we expect that the potentiation of PD-1 activity may offer a promising therapeutic strategy for managing inflammatory and autoimmune diseases. Our current findings provide a rationale for strategies seeking to enhance the inhibitory effect of PD-1 by increasing its expression level.
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
52
開始ページ
19896
終了ページ
19906
発行日
2019-11-13
備考
内容要旨・審査要旨・論文本文の公開
本論文は,著者Natsumi 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. Natsumi Maeda, Takumi Maruhashi, Daisuke Sugiura, Kenji Shimizu, Il-mi Okazaki, and Taku Okazaki. Glucocorticoids potentiate the inhibitory capacity of programmed cell death 1 by up-regulating its expression on T cells. J Biol Chem. 2019; 294(52):19896-19906.
権利情報
© the Author(s).
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3358号
学位記番号
甲医第1441号
学位授与年月日
2020-03-23
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