慢性乙型肝炎通过多酚体外治疗对HBV特异性CD8 T细胞的功能重

StephenW

Functional reconstitution of HBV-specific CD8 T cells by in vitro polyphenol treatment in chronic hepatitis B

    Greta Acerbi
    Ilaria Montali
    Gennaro Domenico Ferrigno
    Daniele Del Rio
    Carlo Ferrari
    Paola Fisicaro
    Show all authors

Open AccessPublished:November 11, 2020DOI:https://doi.org/10.1016/j.jhep.2020.10.034
Highlights

    •
    HBV-specific CD8 T cells display altered autophagic flux in chronic hepatitis B.
    •
    Resveratrol and oleuropein can improve mitochondrial function and proteostasis in CD8 T cells.
    •
    Polyphenol metabolites exert an effect comparable with parental molecules.
    •
    A combination of polyphenols and antioxidants further improves CD8 T cell responses.

Background & Aims
In chronic HBV infection, mitochondrial functions and proteostasis are dysregulated in exhausted HBV-specific CD8 T cells. To better characterise the potential involvement of deregulated protein degradation mechanisms in T cell exhaustion, we analysed lysosome-mediated autophagy in HBV-specific CD8 T cells. Bioactive compounds able to simultaneously target both mitochondrial functions and proteostasis were tested to identify optimal combination strategies to reconstitute efficient antiviral CD8 T cell responses in patients with chronic HBV infection.
Methods
Lysosome-mediated degradation pathways were analysed by flow cytometry in virus-specific CD8 T cells from patients with chronic HBV infection. Mitochondrial function, intracellular proteostasis, and cytokine production were evaluated in HBV-peptide-stimulated T cell cultures, in the presence or absence of the polyphenols resveratrol (RSV) and oleuropein (OLE) and their metabolites, either alone or in combination with other bioactive compounds.
Results
HBV-specific CD8 T cells from patients with CHB showed impaired autophagic flux. RSV and OLE elicited a significant improvement in mitochondrial, proteostasis and antiviral functions in CD8 T cells. Cytokine production was also enhanced by synthetic metabolites, which correspond to those generated by RSV and OLE metabolism in vivo, suggesting that these polyphenols may also display an effect after transformation in vivo. Moreover, polyphenolic compounds improved the T cell revitalising effect of mitochondria-targeted antioxidants and of programmed cell death protein 1/programmed cell death ligand 1 blockade.
Conclusions
Simultaneously targeting multiple altered intracellular pathways with the combination of mitochondria-targeted antioxidants and natural polyphenols may represent a promising immune reconstitution strategy for the treatment of chronic HBV infection.
Lay summary
In chronic hepatitis B, antiviral T lymphocytes are deeply impaired, with many altered intracellular functions. In vitro exposure to polyphenols, such as resveratrol and oleuropein, can correct some of the deregulated intracellular pathways and improve antiviral T cell function. This effect can be further strengthened by the association of polyphenols with antioxidant compounds in a significant proportion of patients. Thus, the combination of antioxidants and natural polyphenols represents a promising strategy for chronic hepatitis B therapy.

StephenW

慢性乙型肝炎通过多酚体外治疗对HBV特异性CD8 T细胞的功能重建

    格雷塔·阿切尔比（Greta Acerbi）
    伊拉里亚·蒙塔利（Ilaria Montali）
    根纳罗·多梅尼科·费里尼奥
    丹妮尔·德尔里约（Daniele Del Rio）
    卡罗·法拉利（Carlo Ferrari）
    保拉·费斯卡罗（Paola Fisicaro）
    显示所有作者

开放获取发布时间：2020年11月11日DOI：https：//doi.org/10.1016/j.jhep.2020.10.034
强调

    •
    HBV特异性CD8 T细胞在慢性乙型肝炎中显示出自噬通量改变。
    •
    白藜芦醇和橄榄苦苷可以改善CD8 T细胞中的线粒体功能和蛋白稳态。
    •
    多酚代谢物的作用可与亲代分子媲美。
    •
    多酚和抗氧化剂的组合可进一步改善CD8 T细胞反应。

背景与目标
在慢性HBV感染中，精疲力竭的HBV特异性CD8 T细胞的线粒体功能和蛋白稳态失调。为了更好地表征失调的蛋白质降解机制在T细胞衰竭中的潜在参与，我们分析了HBV特异性CD8 T细胞中的溶酶体介导的自噬。测试了能够同时靶向线粒体功能和蛋白稳态的生物活性化合物，以鉴定最佳组合策略，以重建慢性HBV感染患者的有效抗病毒CD8 T细胞应答。
方法
通过流式细胞术分析了慢性HBV感染患者的病毒特异性CD8 T细胞中的溶酶体介导的降解途径。在存在或不存在多酚白藜芦醇（RSV）和橄榄苦苷（OLE）及其代谢物的情况下，单独或与其他生物活性物质联合使用时，在HBV肽刺激的T细胞培养中评估线粒体功能，细胞内蛋白变形和细胞因子的产生化合物。
结果
CHB患者的HBV特异性CD8 T细胞显示自噬通量受损。 RSV和OLE引起CD8 T细胞中线粒体，蛋白稳定和抗病毒功能的显着改善。合成代谢物也可增强细胞因子的产生，合成代谢物与体内RSV和OLE代谢产生的代谢物相对应，表明这些多酚在体内转化后也可能发挥作用。此外，多酚化合物改善了针对线粒体的抗氧化剂和程序性细胞死亡蛋白1 /程序性细胞死亡配体1封锁的T细胞恢复活力。
结论
线粒体靶向的抗氧化剂和天然多酚的组合同时靶向多种改变的细胞内途径，可能代表了一种有前途的免疫重建策略，可用于治疗慢性HBV感染。
放置摘要
在慢性乙型肝炎中，抗病毒T淋巴细胞受损严重，细胞内功能发生许多变化。体外暴露于多酚，例如白藜芦醇和橄榄苦苷，可以纠正一些失控的细胞内途径并改善抗病毒T细胞功能。通过在相当多的患者中将多酚与抗氧化剂结合，可以进一步增强这种效果。因此，抗氧化剂和天然多酚的结合代表了慢性乙型肝炎治疗的一种有前途的策略。

StephenW

https://www.journal-of-hepatolog ... 8278(20)33751-X/pdf