Glucocorticoids potentiate the inhibitory capacity of programmed cell death 1 by up-regulating its expression on T cells

• Material Type: 博士論文
• Title: Glucocorticoids potentiate the inhibitory capacity of programmed cell death 1 by up-regulating its expression on T cells
• Author/Editor: Maeda, Natsumi; Maruhashi, Takumi; Sugiura, Daisuke; Shimizu, Kenji; Okazaki, Il-mi; Okazaki, Taku
• Author Heading: Maeda, Natsumi; Maruhashi, Takumi; Sugiura, Daisuke; Shimizu, Kenji; Okazaki, Il-mi; Okazaki, Taku
• Publication, Distribution, etc.: American Society for Biochemistry and Molecular Biology
• Publication Date: 2019-11-13
• Publication Date (W3CDTF): 2019-11-13
• Alternative Title: 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
• Periodical title: Journal of Biological Chemistry
• No. or year of volume/issue: 294 52
• Volume: 294
• Issue: 52
• Pages: 19896-19906
• ISSN (Periodical Title): ISSN : 1083-351X
• Degree grantor/type: 徳島大学
• Date Granted: 2020-03-23
• Dissertation Number: 甲第3358号
• Degree Type: 博士（医学）
• Text Language Code: eng
• Subject Heading: immunology; immunosuppression; T cell; T cell receptor; gene expression; glucocorticoid; cytokine induction; PD-1; co-receptor; immune-checkpoint
• Target Audience: 一般
• Note (General): 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.
• Format (IMT): application/pdf
• Access Restrictions: インターネット公開
• Rights (production): © the Author(s).
• Related Material (DOI): 10.1074/jbc.RA119.010379
• 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

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