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ID 113693
Title Alternative
PD-1は自己反応性CD8陽性T細胞の活性化経路を遮断して細胞傷害機能の獲得を阻止する
Author
Okamura, Hikari Tokushima University|Otsuka Pharmaceutical Co., Ltd.
Shimizu, Kenji Tokushima University
Mizuno, Reina Tokushima University
Keywords
抑制性免疫補助受容体
PD-1
1型糖尿病
単一細胞発現解析
擬似時間解析
Type I diabetes
single cell analysis
pseudotime ordering
Content Type
Thesis or Dissertation
Description
Anti-PD-1 therapy can induce eradication of tumors and immune-related adverse events (irAEs) in humans and model animals. However, how anti-PD-1 therapy modifies cellular phenotypes of CD8+ T cells to destroy tumors and damage self-tissues remains to be clarified. Here we performed single-cell mRNA expression profiling of autoreactive CD8+ T cells under or beyond PD-1 suppression in target tissues and reconstructed their activation trajectory. Autoreactive CD8+ T cells went through four activation phases and PD-1 strongly attenuated the transition from the second- to the third-phase, where effector functions were acquired. Shifts in cluster composition of autoreactive CD8+ T cells markedly reflected the severity of autoimmunity. In addition, genes up-regulated along the activation-trajectory in autoimmunity were highly expressed in responders of melanoma patients in anti-PD-1 therapy, suggesting that tumor-specific T cells need to be activated in a similar trajectory to destroy tumors in human patients upon PD-1 blockade. These findings reveal that PD-1 blockade facilitates the activation trajectory of CD8+ T cells to boost their effector functions. Targeted manipulation of the trajectory could lead to new therapeutic opportunities.
Journal Title
Journal of Autoimmunity
ISSN
08968411
10959157
NCID
AA10717368
AA11542328
Publisher
Elsevier Ltd.
Published Date
2019-07-02
Remark
内容要旨・審査要旨・論文本文の公開
本論文は,著者Hikari Okamura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。
Rights
© 2019 The Authors. Published by Elsevier Ltd.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第3322号
Diploma Number
甲医第1424号
Granted Date
2019-07-25
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
Institute of Advanced Medical Sciences