AbstractChronic hepatitis B virus (HBV) infection affects 300 million patients worldwide1,2, in whom virus-specific CD8 T cells by still ill-defined mechanisms lose their function and cannot eliminate HBV-infected hepatocytes3,4,5,6,7. Here we demonstrate that a liver immune rheostat renders virus-specific CD8 T cells refractory to activation and leads to their loss of effector functions.

摘要慢性乙型肝炎病毒（HBV）感染影响全球3亿患者1,2，其中病毒特异性CD8 T细胞通过仍然不明确的机制失去功能，无法消除HBV感染的肝细胞3,4,5,6,7。在这里，我们证明肝脏免疫变阻器使病毒特异性CD8 T细胞难以激活并导致其效应功能丧失。

In preclinical models of persistent infection with hepatotropic viruses such as HBV, dysfunctional virus-specific CXCR6+ CD8 T cells accumulated in the liver and, as a characteristic hallmark, showed enhanced transcriptional activity of cAMP-responsive element modulator (CREM) distinct from T cell exhaustion.

在HBV等嗜肝病毒持续感染的临床前模型中，功能失调的病毒特异性CXCR6+CD8 T细胞积聚在肝脏中，并且作为特征性标志，显示出不同于T细胞耗竭的cAMP反应元件调节剂（CREM）的转录活性增强。

In patients with chronic hepatitis B, circulating and intrahepatic HBV-specific CXCR6+ CD8 T cells with enhanced CREM expression and transcriptional activity were detected at a frequency of 12–22% of HBV-specific CD8 T cells. Knocking out the inhibitory CREM/ICER isoform in T cells, however, failed to rescue T cell immunity.

在慢性乙型肝炎患者中，检测到循环和肝内HBV特异性CXCR6+CD8 T细胞具有增强的CREM表达和转录活性，频率为HBV特异性CD8 T细胞的12-22%。然而，敲除T细胞中的抑制性CREM/ICER同种型未能挽救T细胞免疫力。

This indicates that CREM activity was a consequence, rather than the cause, of loss in T cell function, further supported by the observation of enhanced phosphorylation of protein kinase A (PKA) which is upstream of CREM. Indeed, we found that enhanced cAMP–PKA-signalling from increased T cell adenylyl cyclase activity augmented CREM activity and curbed T cell activation and effector function in persistent hepatic infection.

这表明CREM活性是T细胞功能丧失的结果，而不是原因，这进一步得到了CREM上游蛋白激酶a（PKA）磷酸化增强的观察结果的支持。实际上，我们发现，在持续性肝脏感染中，增加的T细胞腺苷酸环化酶活性增强了cAMP-PKA信号传导，增强了CREM活性，并抑制了T细胞活化和效应子功能。

Mechanistically, CD8 T cells recognizing their antigen on hepatocytes established close and extensive contact with liver sinusoidal endothelial cells, thereby enhancing adenylyl cyclase–cAMP–PKA signalling in T cells. In these hepatic CD8 T cells, which recognize their antigen on hepatocytes, phosphorylation of key signalling kinases of th.

从机制上讲，识别肝细胞抗原的CD8 T细胞与肝窦内皮细胞建立了紧密而广泛的接触，从而增强了T细胞中腺苷酸环化酶-cAMP-PKA的信号传导。在这些识别肝细胞抗原的肝CD8 T细胞中，th的关键信号激酶磷酸化。

MainCD8 T cells are key in the control of hepatitis B virus (HBV) infection of the liver and kill infected hepatocytes3 but, during chronic infection, virus-specific CD8 T cells are dysfunctional and fail to eliminate infected hepatocytes. Spontaneous regain of immune control of infection in a few patients with chronic hepatitis B indicates that loss of virus-specific T cell function in these patients is reversible8,9 and is not necessarily epigenetically programmed as observed for exhausted virus-specific T cells10.

主要CD8 T细胞是控制肝脏乙型肝炎病毒（HBV）感染并杀死感染肝细胞的关键3，但在慢性感染期间，病毒特异性CD8 T细胞功能失调，无法消除感染的肝细胞。少数慢性乙型肝炎患者感染免疫控制的自发恢复表明，这些患者病毒特异性T细胞功能的丧失是可逆的[8,9]，并且不一定像耗尽的病毒特异性T细胞所观察到的那样进行表观遗传编程10。

Attempts to strengthen virus-specific immunity by immune therapies, such as therapeutic vaccination, are considered promising approaches to restore virus-specific CD8 T cell function in patients with chronic hepatitis B11,12,13,14,15. It remains largely unclear, however, what causes the loss of virus-specific CD8 T cell function in the liver during persistent hepatocyte infection.CREM-expressing CXCR6+ CD8 T cells in persistent HBVIt is difficult to study the mechanisms curbing antiviral T cell immunity during chronic hepatitis B because of the scarcity of virus-specific CD8 T cells16,17,18.

通过免疫疗法（例如治疗性疫苗接种）增强病毒特异性免疫的尝试被认为是恢复慢性肝炎患者病毒特异性CD8 T细胞功能的有希望的方法B11,12,13,14,15。然而，在持续性肝细胞感染期间，是什么导致肝脏中病毒特异性CD8 T细胞功能丧失，目前尚不清楚。由于缺乏病毒特异性CD8 T细胞16,17,18，在持续性HBVIt中表达CREM的CXCR6+CD8 T细胞很难研究在慢性乙型肝炎期间抑制抗病毒T细胞免疫的机制。

Therefore, we established a model of persistent infection compared to acute-resolved infection with viruses that target and replicate specifically in hepatocytes. We generated two hepatotropic recombinant adenoviruses encoding ovalbumin, green fluorescence protein (GFP) and luciferase (GOL)19. These adenoviruses differed in their promoters driving viral gene expression and the outcome of infection, a cytomegalovirus promoter (Ad–CMV–GOL) leading to acute resolved infection with transient liver damage compared to a hepatocyte-specific transthyretin promoter (Ad–TTR–GOL) leading to persistent infection with continuous low-level liver damage (Fig.

因此，我们建立了一个持续感染的模型，与急性消退的病毒感染相比，这些病毒特异性靶向并在肝细胞中复制。我们产生了两种编码卵清蛋白，绿色荧光蛋白（GFP）和荧光素酶（GOL）19的嗜肝重组腺病毒。这些腺病毒在驱动病毒基因表达和感染结果的启动子上有所不同，巨细胞病毒启动子（Ad-CMV-GOL）与肝细胞特异性运甲状腺素蛋白启动子（Ad-TTR-GOL）相比，导致急性消退感染并伴有短暂性肝损伤，导致持续性低水平肝损伤（图）。

1a and Extended Data Fig..

。。

Data availability

数据可用性

RNA-seq data for mouse HBcore-specific CD8 T cells are deposited in the Gene Expression Omnibus (GEO) at accessions GSE214151 and GSE233661. RNA-seq data for mouse ovalbumin-specific CD8 T cells are deposited at GSE168096. RNA-seq data for mouse LCMV-specific CD8 T cells are deposited at GSE212925. RNA-seq data for human HBV-specific CD8 T cells are available at Figshare (https://figshare.com/s/245d38cb7c4901b70b3f (ref.

小鼠HBcore特异性CD8 T细胞的RNA-seq数据保存在基因表达综合（GEO）中，位于GSE214151和GSE233661。小鼠卵清蛋白特异性CD8 T细胞的RNA-seq数据保存在GSE168096。小鼠LCMV特异性CD8 T细胞的RNA-seq数据保存在GSE212925。人类HBV特异性CD8 T细胞的RNA-seq数据可在Figshare获得(https://figshare.com/s/245d38cb7c4901b70b3f（参考。

88) and https://figshare.com/s/0198184966164a2aabf4 (ref. 89)). All high-content data shown in this manuscript are deposited at publicly available databases (Extended Data). Source data are provided with this paper..

88）和https://figshare.com/s/0198184966164a2aabf4（参考文献89））。。本文提供了源数据。。

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Download referencesAcknowledgementsWe thank the LiverConsortium, supported by Janssen Pharma, for providing data on intrahepatic CD8 T cells isolated from patients with chronic hepatitis B. We thank the tissue bank from the Institute of Pathology, School of Medicine and Health at TUM for contributing human liver tissue samples.

下载参考文献致谢我们感谢Janssen Pharma支持的LiverConsortium提供了从慢性乙型肝炎患者中分离出的肝内CD8 T细胞的数据。我们感谢TUM医学与健康学院病理学研究所的组织库提供了人类肝脏组织样本。

This study was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) (CRC-TRR179 to P.A.K., U.P., M.H., R.T., C.H. and D.W.; CRC1160 to M.H.; CRC1371, CRC1054, ZE 832/6-1 and ZE 832/8-1 to D.Z.; DFG grants 424926990 and 442405234 to J.P.B.; and DFG grants INST 95/1763-1, 95/1738-1 and 95-1651-1 to P.A.K.), by grants from the German Center for Infection Research Munich site (P.A.K., U.P.

这项研究得到了德国科学基金会（DFG）的资助（CRC-TRR179授予P.A.K.，U.P.，M.H.，R.T.，C.H.和D.W.；CRC1160授予M.H.；CRC1371，CRC1054，ZE 832/6-1和ZE 832/8-1授予D.Z.；DFG授予J.P.B 424926990和442405234.；DFG授予INST 95/1763-1、95/1738-1和95-1651-1授予P.A.K.）慕尼黑感染研究网站（P.A.K.，U.P。

and D.W.) and by the EU (TherVacB to U.P. and P.A.K.) and ERC AG to GB 786462. M.H. was supported by the DFG Heisenberg programme, A.O. was supported by the Swiss National Science Foundation (SNSF), grant 310030_146140 and P.J.M. was supported by FOR2599 and CRC-TRR127.FundingOpen access funding provided by Technische Universität München.Author informationAuthor notesThese authors contributed equally: Miriam Bosch, Nina KallinAuthors and AffiliationsInstitute of Molecular Immunology, School of Medicine and Health, Technical University of Munich (TUM), Munich, GermanyMiriam Bosch, Nina Kallin, Sainitin Donakonda, Hannah Wintersteller, Silke Hegenbarth, Anna Fürst, Sutirtha Chattopadhyay, Philippa Meiser, Katrin Manske, Annika Schneider, Vincent Steinbacher, Jan P.

和D.W.）以及欧盟（TherVacB to U.P.和P.A.K.）和ERC AG to GB 786462。M、 H.得到了DFG海森堡计划的支持，A.O.得到了瑞士国家科学基金会（SNSF）的支持，grant 310030\u 146140和P.J.M.得到了FOR2599和CRC-TRR127.FundingOpen access资助的支持，由慕尼黑工业大学提供。作者信息作者注意到这些作者做出了同样的贡献：米里亚姆·博世（Miriam Bosch），尼娜·卡林纳斯（Nina KallinAuthors）及其附属机构慕尼黑工业大学（TUM）医学与健康学院分子免疫学研究所，慕尼黑，德国米里亚姆·博世（GermanyMiriam Bosch），尼娜·卡林（Nina Kallin），赛尼汀·多纳康达（Sainitin Donakonda），汉娜·温特斯特勒（Hannah Wintersteller），西尔克·黑根巴特（Silke Hegenbarth），安娜·福斯特（Anna Fürst），萨蒂尔莎·查托帕迪亚（Sutirtha。

Böttcher, Dirk Wohlleber & Percy A. KnolleRoche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Basel, SwitzerlandJitao David Zhang, Nadine Kumpesa, Vera Griesser, Jean-Christophe Hoflack, Juliane Siebourg-Polster & Souphalone LuangsayThird.

Böttcher，Dirk Wohlleber＆Percy A.KnolleRoche Pharmaceutical Research and Early Development（pRED），罗氏创新中心巴塞尔，巴塞尔，瑞士大卫·张，Nadine Kumpesa，Vera Griesser，Jean-Christophe Hoflack，Juliane Siebourg Polster＆Souphalone Luangsaythrth。

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PubMed Google ScholarContributionsM.B., N. Kallin, H.W., S.H., K.H., A.F., N. Kumpesa, V.G., J.-C.H., L.S., L.J.P., P.M., K.M., A.K., A.S., V.S., Y.T., M.V., E.C., R.Ö., T.E., K.S., A.D.K. and J.S.-P. performed the experiments. A.J.G., A.B., H.L.A.J., B.H., G.M.L., M.H. and R.T.

PubMed谷歌学术贡献。B、 ，N.Kallin，H.W.，S.H.，K.H.，A.F.，N.Kumpesa，V.G.，J.-C.H.，L.S.，L.J.P.，P.M.，K.M.，A.K.，A.S.，V.S.，Y.T.，M.V.，E.C.，R.Ö。，T、 E.，K.S.，A.D.K.和J.S.-P.进行了实验。A、 J.G.，A.B.，H.L.A.J.，B.H.，G.M.L.，M.H.和R.T。

provided essential reagents or data for analysis. S.D., J.D.Z., C.R., E.I.L., M.F., S.C., C.M., G.P.d.A., I.S., J.S., F.T., R.R., A.O., W.-L.L., V.K., G.B., M.K.M., R.H., P.J.M., R.T., C.H., U.P., J.P.B., D.Z., D.W., G.M.L., S.L. and P.A.K. analysed data. M.B., S.D., J.D.Z., P.J.M., M.K.M., R.T., G.M.L., S.L., U.P.

提供用于分析的基本试剂或数据。S、 D.，J.D.Z.，C.R.，E.I.L.，M.F.，S.C.，C.M.，G.P.D.A.，I.S.，J.S.，F.T.，R.R.，A.O.，W.-L.L.，V.K.，G.B.，M.K.M.，R.H.，P.J.M.，R.T.，C.H.，U.P.，J.P.B.，D.Z.，D.W.，G.M.L.，S.L.和P.A.K.分析数据。M、 B.，S.D.，J.D.Z.，P.J.M.，M.K.M.，R.T.，G.M.L.，S.L.，U.P。

and P.A.K. wrote the manuscript.Corresponding authorCorrespondence to.

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Percy A. Knolle.Ethics declarations

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The authors declare no competing interests.

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Nature thanks Antonio Bertoletti, Tobias Bopp, Arash Grakoui and Cliona OʼFarrelly for their contribution to the peer review of this work. Peer reviewer reports are available.

《自然》杂志感谢安东尼奥·贝托莱蒂（AntonioBertoletti）、托拜厄斯·波普（TobiasBopp）、阿拉什·格拉科伊（ArashGrakoui）和克利奥娜·奥法雷利（ClionaO'Farrelly）为这项工作的同行评审所作的贡献。同行评审报告可供查阅。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Extended data figures and tablesExtended Data Fig. 1 Kinetics of infection and frequencies of antigen-specific CD8 T cells during hepatotropic adenoviral infection.a,b, In vivo bioluminescence imaging kinetic after hepatotropic infection and quantification (two-way ANOVA with Tukey’s multiple comparisons; d0: resolved vs.

Additional informationPublisher的注释Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。扩展数据图和表扩展数据图1嗜肝腺病毒感染期间感染的动力学和抗原特异性CD8 T细胞的频率。a，b，嗜肝感染后的体内生物发光成像动力学和定量（双向ANOVA与Tukey多重比较；d0：解析vs。

chronic Padj=0.9295, resolved vs. uninfected Padj=0.0959, chronic vs. uninfected Padj=0.1498; d1: resolved vs. chronic Padj=0.9902, resolved vs. uninfected Padj=0.0209, chronic vs. uninfected Padj=0.1021; d3: resolved vs. chronic Padj=0.2179, resolved vs. uninfected Padj=0.1025, chronic vs. uninfected Padj=0.1269; d5: resolved vs.

慢性Padj=0.9295，消退与未感染Padj=0.0959，慢性与未感染Padj=0.1498；d1：解决与慢性Padj=0.9902，解决与未感染Padj=0.0209，慢性与未感染Padj=0.1021；d3：解决与慢性Padj=0.2179，解决与未感染Padj=0.1025，慢性与未感染Padj=0.1269；d5：解决vs。

chronic Padj=0.1413, resolved vs. uninfected Padj=0.1270, chronic vs. uninfected Padj=0.0168; d7: resolved vs. chronic: Padj=0.8271, resolved vs. uninfected Padj=0.5733, chronic vs. uninfected Padj=0.1293; d17: resolved vs. chronic Padj=0.3965, resolved vs. uninfected Padj=0.6564, chronic vs. uninfected Padj=0.3961; d46: resolved vs.

慢性Padj=0.1413，消退与未感染Padj=0.1270，慢性与未感染Padj=0.0168；d7：解决与慢性：Padj=0.8271，解决与未感染Padj=0.5733，慢性与未感染Padj=0.1293；d17：解决与慢性Padj=0.3965，解决与未感染Padj=0.6564，慢性与未感染Padj=0.3961；d46：解决vs。

chronic Padj=0.0218, resolved vs. uninfected Padj=0.0766, chronic vs. uninfected Padj=0.0219; d98: resolved vs. chronic Padj=0.0087, resolved vs. uninfected Padj=0.8296, chronic vs. uninfected Padj=0.0087; n = 5). c, Quantification of adenoviral copies in liver tissue (two-way ANOVA with Sidak’s multiple comparison, resolved vs.

慢性Padj=0.0218，消退与未感染Padj=0.0766，慢性与未感染Padj=0.0219；d98：解决与慢性Padj=0.0087，解决与未感染Padj=0.8296，慢性与未感染Padj=0.0087；n=5）。c、 。

chronic Padj<0.0001 for all timepoints, n = 4). d,e, Liver immunohistochemistry detecting GFP-expressing virus-infected hepatocytes in brown (scale bar 50 µm) and quantification (two-way ANOVA with Tukey’s multiple comparisons for Padj, n = 3). f, Time kinetics of sALT (two-way ANOVA with Tukey’s multiple comparison, .

所有时间点的慢性Padj<0.0001，n=4）。d、 e，肝脏免疫组织化学检测棕色（比例尺50μm）中表达GFP的病毒感染的肝细胞和定量（双向ANOVA与Tukey对Padj的多重比较，n=3）。f、 盐的时间动力学（双向方差分析与Tukey的多重比较。

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Hepatitis BViral infection

乙型肝炎病毒感染

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