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ID 114679
Title Alternative
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
Author
Maeda, Natsumi Tokushima University
Maruhashi, Takumi Tokushima University|The University of Tokyo KAKEN Search Researchers
Sugiura, Daisuke Tokushima University|The University of Tokyo KAKEN Search Researchers
Shimizu, Kenji Tokushima University|The University of Tokyo
Okazaki, Il-mi Tokushima University|The University of Tokyo KAKEN Search Researchers
Okazaki, Taku Tokushima University|The University of Tokyo KAKEN Search Researchers
Keywords
immunology
immunosuppression
T cell
T cell receptor
gene expression
glucocorticoid
cytokine induction
PD-1
co-receptor
immune-checkpoint
Content Type
Thesis or Dissertation
Description
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.
Journal Title
Journal of Biological Chemistry
ISSN
1083351X
NCID
AA1202441X
Publisher
American Society for Biochemistry and Molecular Biology
Volume
294
Issue
52
Start Page
19896
End Page
19906
Published Date
2019-11-13
Remark
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.
Rights
© the Author(s).
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第3358号
Diploma Number
甲医第1441号
Granted Date
2020-03-23
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
Institute of Advanced Medical Sciences