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CD40 agonist converting CTL exhaustion via the activation of the mTORC1 pathway enhances PD-1 antagonist action in rescuing exhausted CTLs in chronic infection 期刊论文

编号：

64992048-b92e-4929-a92f-e9ec919f4120
作者：

Xu, Aizhang^[1,2];Wang, Rong^[1,2];Freywald, Andrew^[3];Stewart, Kristoffor^[4];Tikoo, Suresh^[5];Xu, Jianqing(徐建青)^[6]Zheng, Changyu^[7];Xiang, Jim^[1,2];
语种：

English
期刊：

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS ISSN：0006-291X 2017 年 484 卷 3 期 (662 - 667) ; MAR 11
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关键词：

CD40 agonist PD-1 antagonist Chronic infection CTL exhaustion mTORC1 pathway
摘要：

Expansion of PD-1-expressing CD8+ cytotoxic T lymphocytes (CTLs) and associated CTL exhaustion are chief issues for ineffective virus-elimination in chronic infectious diseases. PD-1 blockade using antagonistic anti-PD-L1 antibodies results in a moderate conversion of CTL exhaustion. We previously demonstrated that CD40L signaling of ovalbumin (OVA)-specific vaccine, OVA-Texo, converts CTL exhaustion via the activation of the mTORC1 pathway in OVA-expressing adenovirus (AdVova)-infected B6 mice showing CTL inflation and exhaustion. Here, we developed AdVova-infected B6 and transgenic CD11c-DTR (termed AdVova-B6 and AdVova-CD11c-DTR) mice with chronic infection, and assessed a potential effect of CD40 agonist on the conversion of CTL exhaustion and on a potential enhancement of PD-1 antagonist action in rescuing exhausted CTLs in our chronic infection models. We demonstrate that a single dose of anti-CD40 alone can effectively convert CTL exhaustion by activating the mTORC1 pathway, leading to CTL proliferation, up-regulation of an effector-cytokine IFN-gamma and the cytolytic effect in AdVova-B6 mice. Using anti-CD4 antibody and diphtheria toxin (DT) to deplete CD4+ T-cells and dendritic cells (DCs), we discovered that the CD40 agonist-induced conversion in AdVova-B6 and AdVova-CD11c-DTR mice is dependent upon host CD4+ T-cell and DC involvements. Moreover, CD40 agonist significantly enhances PD-1 antagonist effectiveness in rescuing exhausted CTLs in chronic infection. Taken together, our data demonstrate the importance of CD40 signaling in the conversion of CTL exhaustion and its ability to enhance PD-1 antagonist action in rescuing exhausted CTLs in chronic infection. Therefore, our findings may positively impact the design of new therapeutic strategies for chronic infectious diseases. (C) 2017 Elsevier Inc. All rights reserved.
推荐引用方式
GB/T 7714：

Xu Aizhang,Wang Rong,Freywald Andrew, et al. CD40 agonist converting CTL exhaustion via the activation of the mTORC1 pathway enhances PD-1 antagonist action in rescuing exhausted CTLs in chronic infection [J].BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,2017,484(3):662-667.
APA：

Xu Aizhang,Wang Rong,Freywald Andrew,Stewart Kristoffor,&Xiang Jim.(2017).CD40 agonist converting CTL exhaustion via the activation of the mTORC1 pathway enhances PD-1 antagonist action in rescuing exhausted CTLs in chronic infection .BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,484(3):662-667.
MLA：

Xu Aizhang, et al. "CD40 agonist converting CTL exhaustion via the activation of the mTORC1 pathway enhances PD-1 antagonist action in rescuing exhausted CTLs in chronic infection" .BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 484,3(2017):662-667.

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