Programmed cell death protein-1 (PD-1) protects liver damage by suppressing IFN-γ expression in T cells in infants and neonatal mice.
Programmed cell death protein-1 (PD-1) protects liver damage by suppressing IFN-γ expression in T cells in infants and neonatal mice.
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程序性细胞死亡蛋白-1 (PD-1) 通过抑制婴儿和新生小鼠 T 细胞中的 IFN-γ 表达来保护肝损伤
DOI：
10.1186/s12887-021-02794-x
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发表时间：
2021-07-16
期刊：
影响因子：
2.4
通讯作者：
Xu Y
中科院分区：
文献类型：
--
作者：
Guo X;Xu Y;Luo W;Fang R;Cai L;Wang P;Zhang Y;Wen Z;Xu Y
胆道闭锁（BA）是一种严重的胆道疾病，可能由病毒诱导和免疫介导的胆道系统损伤引起。IFN-γ由CD4+ Th1细胞和CD8+细胞毒性T细胞分泌，是肝脏病理的主要介质。程序性死亡蛋白-1 （PD-1）信号传导抑制T细胞功能。然而，PD-1如何在BA中改变T细胞功能仍不完全清楚。分析BA和对照组肝脏和血液中PD-1表达CD4+和CD8+ T细胞的频率。测定PD-1+CD4+/CD8+T细胞丰度与肝功能指标的相关性。在恒河轮状病毒（RRV）诱导的BA模型中，通过给药抗PD-1抗体来检测PD-1的功能。分析生存率、组织学、直接胆红素、肝免疫细胞亚群和细胞因子的产生。与对照组相比，BA患者CD4+和CD8+ T细胞中PD-1表达明显上调。T细胞中PD-1表达与肝脏中IFN-γ浓度呈负相关（肝脏中PD-1+CD4+T细胞与IFN-γ浓度，r = - 0.25, p = 0.05；肝脏中PD-1+CD8+T细胞与IFN-γ浓度，r = - 0.39, p = 0.004）。阻断PD-1可增加CD4+T和CD8+T细胞中IFN-γ的表达（RRV与抗PD-1处理的RRV小鼠：肝脏CD4+T细胞中IFN-γ+的表达为11.59±3.43%比21.26±5.32%,p = 0.0003；肝脏CD8+T细胞中IFN-γ+的表达为9.33±4.03%比22.55±7.47%,p = 0.0001），抑制胆红素的产生（RRV与抗PD-1处理的RRV小鼠：总胆红素285.4±47.93比229.8±45.86 μmol/L, p = 0.01），加重肝脏免疫病理。PD-1通过抑制T细胞中IFN-γ的产生在BA婴儿中发挥保护作用。增加PD-1信号可以作为治疗BA的策略。在线版本包含补充材料，可在10.1186/s12887-021-02794-x获得。
Biliary atresia (BA) is a severe cholangiopathy possibly resulting from virus-induced and immune-mediated injury of the biliary system. IFN-γ, secreted from CD4+ Th1 cells and CD8+ cytotoxic T cells, is a major mediator of liver pathology. Programmed death protein-1 (PD-1) signaling suppresses T cell function. However, how PD-1 modify T cell function in BA remains incompletely understood. Frequencies of PD-1 expressing CD4+ and CD8+ T cells were analyzed in the liver and blood from BA and control subjects. Associations of PD-1+CD4+/CD8+T cell abundances with liver function indices were measured. Function of PD-1 was measured by administration of an anti-PD-1 antibody in a Rhesus Rotavirus (RRV)-induced BA model. Survival, histology, direct bilirubin, liver immune cell subsets and cytokine production were analyzed. PD-1 was significantly upregulated in CD4+ and CD8+ T cells in patients with BA compared with control subjects. PD-1 expression in T cells was negatively associated with IFN-γ concentration in liver (PD-1+CD4+T cells in liver vs. IFN-γ concentration, r = − 0.25, p = 0.05; PD-1+CD8+T cells in liver vs. IFN-γ concentration, r = − 0.39, p = 0.004). Blockade of PD-1 increased IFN-γ expression in CD4+ T and CD8+ T cells (RRV vs. anti-PD-1 treated RRV mice: 11.59 ± 3.43% vs. 21.26 ± 5.32% IFN-γ+ in hepatic CD4+T cells, p = 0.0003; 9.33 ± 4.03% vs. 22.55 ± 7.47% IFN-γ+ in hepatic CD8+T cells, p = 0.0001), suppressed bilirubin production (RRV vs. anti-PD-1 treated RRV mice: 285.4 ± 47.93 vs. 229.8 ± 45.86 μmol/L total bilirubin, p = 0.01) and exacerbated liver immunopathology. PD-1 plays a protective role in infants with BA by suppressing IFN-γ production in T cells. Increasing PD-1 signaling may serve as a therapeutic strategy for BA. The online version contains supplementary material available at 10.1186/s12887-021-02794-x.
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影响因子：
1.3
作者：
Fjær, RB;Bruu, AL;Nordbo, SA
通讯作者：
Nordbo, SA
影响因子：
13.5
作者：
Wang, WZW;Smith, DLH;Zucker, SD
通讯作者：
Zucker, SD
影响因子：
15.9
作者：
Shivakumar, P;Campbell, KM;Bezerra, JA
通讯作者：
Bezerra, JA
影响因子：
5.1
作者：
GLASER, JH;BALISTRERI, WF;MORECKI, R
通讯作者：
MORECKI, R
DOI：
10.1084/jem.20112741
发表时间：
2012-06-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Yokosuka T;Takamatsu M;Kobayashi-Imanishi W;Hashimoto-Tane A;Azuma M;Saito T
通讯作者：
Saito T