HBV核心特异性与HBV聚合酶特异性CD8 + T细胞在低病毒载量的慢

StephenW

Gut. 2019 Jan 8. pii: gutjnl-2018-316641. doi: 10.1136/gutjnl-2018-316641. [Epub ahead of print]
Phenotypic and functional differences of HBV core-specific versus HBV polymerase-specific CD8+ T cells in chronically HBV-infected patients with low viral load.
Schuch A1,2,3, Salimi Alizei E#1,2,4, Heim K#1,2,3, Wieland D1,2, Kiraithe MM1,2, Kemming J1,2,3, Llewellyn-Lacey S5, Sogukpinar Ö1,2, Ni Y6, Urban S6,7, Zimmermann P1,2,3, Nassal M1,2, Emmerich F8, Price DA5, Bengsch B1,2, Luxenburger H1,2, Neumann-Haefelin C1,2, Hofmann M#1,2, Thimme R#1,2.
Author information

1
    Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.
2
    Faculty of Medicine, University of Freiburg, Freiburg, Germany.
3
    Faculty of Biology, University of Freiburg, Freiburg, Germany.
4
    Faculty of Chemistry and Pharmacy, University of Freiburg, Freiburg, Germany.
5
    Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.
6
    Department of Infectious Diseases, Molecular Virology, Heidelberg University Hospital, Heidelberg, Germany.
7
    German Center for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, Germany.
8
    Institute for Cell and Gene Therapy, University Hospital Freiburg, Freiburg, Germany.
#
    Contributed equally

Abstract
OBJECTIVE:

A hallmark of chronic HBV (cHBV) infection is the presence of impaired HBV-specific CD8+ T cell responses. Functional T cell exhaustion induced by persistent antigen stimulation is considered a major mechanism underlying this impairment. However, due to their low frequencies in chronic infection, it is currently unknown whether HBV-specific CD8+ T cells targeting different epitopes are similarly impaired and share molecular profiles indicative of T cell exhaustion.
DESIGN:

By applying peptide-loaded MHC I tetramer-based enrichment, we could detect HBV-specific CD8+ T cells targeting epitopes in the HBV core and the polymerase proteins in the majority of 85 tested cHBV patients with low viral loads. Lower detection rates were obtained for envelope-specific CD8+ T cells. Subsequently, we performed phenotypic and functional in-depth analyses.
RESULTS:

HBV-specific CD8+ T cells are not terminally exhausted but rather exhibit a memory-like phenotype in patients with low viral load possibly reflecting weak ongoing cognate antigen recognition. Moreover, HBV-specific CD8+ T cells targeting core versus polymerase epitopes significantly differed in frequency, phenotype and function. In particular, in comparison with core-specific CD8+ T cells, a higher frequency of polymerase-specific CD8+ T cells expressed CD38, KLRG1 and Eomes accompanied by low T-bet expression and downregulated CD127 indicative of a more severe T cell exhaustion. In addition, polymerase-specific CD8+ T cells exhibited a reduced expansion capacity that was linked to a dysbalanced TCF1/BCL2 expression.
CONCLUSIONS:

Overall, the molecular mechanisms underlying impaired T cell responses differ with respect to the targeted HBV antigens. These results have potential implications for immunotherapeutic approaches in HBV cure.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
KEYWORDS:

BCL-2 family proteins; T lymphocytes; chronic viral hepatitis; hepatitis B; immune response

PMID:
    30622109
DOI:
    10.1136/gutjnl-2018-316641

StephenW

肠道。 2019年1月8日.pii：gutjnl-2018-316641。 doi：10.1136 / gutjnl-2018-316641。 [提前打印]
HBV核心特异性与HBV聚合酶特异性CD8 + T细胞在低病毒载量的慢性HBV感染患者中的表型和功能差异。
Schuch A1,2,3，Salimi Alizei E＃1,2,4，Heim K＃1,2,3，Wieland D1,2，Kiraithe MM1,2，Kemming J1,2,3，Llewellyn-Lacey S5，SogukpinarÖ1 ，2，Ni Y6，Urban S6,7，Zimmermann P1,2,3，Nassal M1,2，Emmerich F8，价格DA5，Bengsch B1,2，Luxenburger H1,2，Neumann-Haefelin C1,2，Hofmann M＃1 ，2，Thimme R＃1,2。
作者信息

1
    德国弗莱堡弗赖堡大学医院医学系二。
2
    弗莱堡大学医学院，弗莱堡，德国。
3
    德国弗赖堡弗莱堡大学生物系。
4
    德国弗莱堡弗莱堡大学化学与药学院。
五
    英国卡迪夫卡迪夫大学医学院感染与免疫研究所。
6
    德国海德堡海德堡大学医院传染病科，分子病毒学系。
7
    德国感染研究中心（DZIF），合作伙伴Site Heidelberg，德国海德堡。
8
    德国弗赖堡弗莱堡大学医院细胞与基因治疗研究所。
＃
    贡献一致

抽象
目的：

慢性HBV（cHBV）感染的标志是HBV特异性CD8 + T细胞应答受损。由持久性抗原刺激诱导的功能性T细胞耗竭被认为是这种损伤的主要机制。然而，由于它们在慢性感染中的低频率，目前尚不清楚靶向不同表位的HBV特异性CD8 + T细胞是否同样受损并且共享指示T细胞耗竭的分子谱。
设计：

通过应用肽加载的MHC I四聚体富集，我们可以检测HBV核心中的表位的HBV特异性CD8 + T细胞和大多数具有低病毒载量的85名测试的cHBV患者中的聚合酶蛋白。获得了包膜特异性CD8 + T细胞的较低检测率。随后，我们进行了表型和功能深入分析。
结果：

HBV特异性CD8 + T细胞并非终末耗尽，而是在具有低病毒载量的患者中表现出记忆样表型，可能反映了弱持续的同源抗原识别。此外，靶向核心与聚合酶表位的HBV特异性CD8 + T细胞在频率，表型和功能方面显着不同。特别地，与核心特异性CD8 + T细胞相比，更高频率的聚合酶特异性CD8 + T细胞表达CD38，KLRG1和Eome，伴有低T-bet表达和下调CD127，表明更严重的T细胞衰竭。此外，聚合酶特异性CD8 + T细胞表现出降低的扩增能力，其与TCF1 / BCL2表达失衡有关。
结论：

总体而言，受损的T细胞应答的分子机制与靶向的HBV抗原不同。这些结果对HBV治愈的免疫治疗方法具有潜在意义。

©作者（或其雇主）2019。CC BY-NC允许的重新使用。没有商业再利用。请参阅权限。由BMJ发布。
关键词：

BCL-2家族蛋白; T淋巴细胞;慢性病毒性肝炎;乙型肝炎;免疫反应

结论：
    30622109
DOI：
    10.1136 / gutjnl-2018-316641

StephenW

https://gut.bmj.com/content/gutj ... 018-316641.full.pdf

Significance of this study
What is already known on this subject?

    HBV-specific CD8+ T cells play a central role in the elimination of HBV infection.

    Frequencies of HBV-specific CD8+ T cells in chronic HBV infection are very low reflected by low detection rates applying ex vivo peptide-loaded MHC I (pMHC I) tetramer staining.

    Detectable HBV-specific CD8+ T cells are functionally impaired, exhibit mitochondrial alterations, express inhibitory receptors and display dysregulation of T-bet.

What are the new findings?

    By applying a pMHC I tetramer-based enrichment strategy, we could detect HBV-specific CD8+ T cells in the majority of chronically HBV-infected patients.

    Env183-specific CD8+ T cells are hardly detectable by pMHC I tetramer-based enrichment in chronically HBV-infected patients.

    HBV-specific CD8+ T cells targeting core18/141and pol455/173 epitopes are not terminally exhausted but predominantly exhibit a memory-like phenotype in chronic infection.

    Core18/141 and pol455/173-specific CD8+ T cells differ in frequency, phenotype and function in chronic HBV infection but not in resolved HBV infection.

    Dysregulated TCF1/BCL2 expression limits the expansion capacity of pol455/173-specific CD8+ T cells in chronic HBV infection.

How might it impact on clinical practice in the foreseeable future?

    These findings have potential implications for the design of T cell-targeted therapeutic approaches in HBV cure.
这项研究的意义
在这个问题上已经知道了什么？

    HBV特异性CD8 + T细胞在消除HBV感染中起重要作用。

    慢性HBV感染中HBV特异性CD8 + T细胞的频率非常低，这是通过应用离体肽加载的MHC I（pMHC I）四聚体染色的低检测率反映的。

    可检测的HBV特异性CD8 + T细胞功能受损，表现出线粒体改变，表达抑制性受体并显示T-bet的失调。

有哪些新发现？

    通过应用基于pMHC I四聚体的富集策略，我们可以检测大多数慢性HBV感染患者中的HBV特异性CD8 + T细胞。

    在长期HBV感染的患者中，通过基于pMHC I四聚体的富集难以检测到Env183特异性CD8 + T细胞。

    靶向核心18/141和pol455 / 173表位的HBV特异性CD8 + T细胞不是末端耗尽的，而是主要在慢性感染中表现出记忆样表型。

    Core18 / 141和pol455 / 173特异性CD8 + T细胞在慢性HBV感染中的频率，表型和功能不同，但在解决的HBV感染中不同。

    失调的TCF1 / BCL2表达限制了pol455 / 173特异性CD8 + T细胞在慢性HBV感染中的扩增能力。

在可预见的未来，它对临床实践有何影响？

    这些发现对于HBV治愈中T细胞靶向治疗方法的设计具有潜在意义。