Prostaglandin E2 facilitates Hepatitis B virus replication by impairing CTL function
Prostaglandin E2 facilitates Hepatitis B virus replication by impairing CTL function
复制标题
前列腺素 E2 通过损害 CTL 功能来促进乙型肝炎病毒复制。
DOI：
10.1016/j.molimm.2018.08.009
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发表时间：
2018-11-01
影响因子：
3.6
通讯作者：
Liang, Xiaohong
中科院分区：
文献类型：
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作者：
Li, Xiaoyan;Xie, Tingting;Liang, Xiaohong
T细胞功能障碍的恢复是治疗慢性疾病的一种新的和有前途的方法。前列腺素E2是研究最多的前列腺素之一，对包括T细胞在内的多种免疫细胞具有强而多样的免疫调节活性，已成为一种有前途的治疗靶点。在这里，我们发现，与健康的捐助者相比，慢性B肝炎病毒（HBV）感染的患者血清前列腺素E2水平显着升高。重要的是，血清PGE 2浓度与慢性B型肝炎（CH B）患者的病毒载量和肝损伤相关。在AAV-HBV 1.2小鼠模型中，给予PGE 2类似物可促进HBV复制，而PGE 2的两个重要受体EP 2和EP 4的拮抗剂可抑制病毒复制。然而，PGE 2类似物对培养的携带HBV的肝细胞系的生长和病毒复制没有显着影响。进一步分析显示，CH B患者中的高PGE 2水平与CD 8 + T细胞中的高Tim-3表达和低水平的穿孔素和颗粒酶B相关。同时，阻断PGE 2信号传导恢复了CD 8 + T细胞的功能并控制了HBV感染。CD 8 + T细胞的耗竭几乎消除了PGE 2对HBV复制的影响。这些发现确定PGE 2作为CD 8 + T细胞的负调节因子，有助于HBV持续存在，并且PGE 2信号传导的干预可能具有潜在的翻译意义。
Reversal of T cell dysfunction is a novel and promising approach for the treatment of chronic diseases. PGE2, one of most studied Prostaglandins, exhibits strong and versatile immunoregulation activity on different immune cells including T cells, and has become a promising therapeutic target. Here we found that compared to healthy donors, patients with chronic Hepatitis B virus (HBV) infection had significantly elevated serum PGE2 level. Importantly, serum PGE2 concentration correlated with viral load and liver damage in Chronic hepatitis B(CHB) patients. In AAV-HBV1.2 mouse model, administration of PGE2 analogue promoted HBV replication, while antagonists for EP2 and EP4, two important receptors for PGE2, inhibited virus replication. However, PGE2 analogue had no significant effect on the growth and virus replication in cultured HBV-harboring hepatocyte cell line. Further analysis showed that high PGE2 level in CHB patients correlated with high Tim-3 expression and low level of perforin and granzme B in CD8 + T cells. In parallel, blockade of PGE2 signaling restored the function of CD8 + T cells and controls HBV infection. Depletion of CD8 + T cells almost abrogated the effects of PGE2 on HBV replication. These findings identify PGE2 as a negative regulator for CD8 + T cells contributing to HBV persistence and the intervention of PGE2 signaling might be of potentially translational significance.