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HBcore-specific CXCR6+CD8 T cells during persistent HBV replication in mice lose their effector function and have high CREM activity

ABSTRACT: We investigated molecular profiles of CD8 T cells in persistent experimental Hepatitis B virus (HBV) infection. To this end, we established a preclinical in vivo model where HBV-replicating hepatocytes were cleared by virus-specific immunity after infection with 107 IU Ad-HBV, whereas persistent HBV replication developed after infection with 108 IU Ad-HBV, revealed by high serum HBeAg levels, high numbers of HBV genome copies and of HBcorepos hepatocytes in liver tissue. To overcome variable surface expression of the T cell receptor during chronic infection and unequivocally identify HBV-specific CD8 T cells, we adoptively transferred naïve CD45.1+HBcore-specific CD8 T cells from Cor93 transgenic mice (HBcoreCD8 T cells) the day before Ad-HBV infection. After clearance of HBV-replicating hepatocytes (d44 p.i.), liver CD45.1+HBcoreCD8 T cells expressed either CXCR6 or CX3CR1, and in the spleen only CX3CR1+ CD8 T cells were detected. Next, we evaluated the transcriptional profile of FACSorted HBcoreCD8 T cells after resolved compared to persistent infection employing SmartSeq2. The resulting dataset is reported here.

ORGANISM(S): Mus musculus

PROVIDER: GSE214151 | GEO | 2024/05/08

REPOSITORIES: GEO

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Project description:Chronic viral hepatitis after infection with hepatotropic viruses like hepatitis B virus (HBV) affects 300 million persons worldwide, which as the result of chronic immune-mediated hepatic inflammation cause liver cirrhosis and cancer being responsible for 800.000 deaths per year3. Chronic viral hepatitis is maintained by failure of the host´s immune response to control viral infection, but the mechanisms for this inability of virus-specific CD8 T cells to eliminate HBV-infected hepatocytes remain unclear. Here, we demonstrate that during persistent experimental infection with hepatotropic viruses and HBV replication in hepatocytes all virus-specific CD8 T cells present in the liver expressed the tissue-residency markers CXCR6 and CD69. However, RNAseq analysis revealed that CXCR6+CD8 T cells during persistent hepatotropic infection were retained in the liver because of antigen-recognition rather than a transcriptional tissue-residency program, in contrast to canonical liver-resident memory CXCR6+CD8 T cells emerging after resolved infection. Whereas during persistent infection with a model virus like lymphocytic choriomeningitis virus with broad tissue and cell tropism exhausted CD8 T cells show graded loss of effector functions, hepatic virus-specific CXCR6+CD8 T cells during persistent infection with hepatotropic viruses were blinded and completely non-responsive to stimulation in absence of a canonical tox exhaustion signature. Rather, in blinded liver CXCR6+CD8 T cells, transcription factor network analysis revealed Crem, the cAMP-responsive-element-modulator, as the only transcription factor discreetly active in CD8 T cells with complete loss of effector function during persistent hepatotropic infection. Similarly, single cell RNA-sequencing of peripheral blood HBcore-specific CD8 T cells from chronic hepatitis B patients also revealed enhanced CREM activity. Notably, knock-out of the inhibitory CREM/ICER gene in T cells failed to rescue protective T cell immunity during persistent infection with hepatotropic viruses pointing towards post-translational mechanisms relevant for enhanced Crem activity and loss of effector function. Indeed, T cell receptor-associated signalling was blocked in blinded antigen-specific CXCR6+CD8 T cells, that in situ during persistent hepatotropic infection were in close proximity to liver sinusoidal endothelial cells producing high amounts of cAMP-inducing prostanoids. Inhibitory cAMP/PKA/CSK activity increased CREM activity and disconnected CXCR6+CD8 T cells from activation signalling through the T cell receptor. Thus, enhanced CREM expression identifies blinded liver CXCR6+CD8 T cells, but loss of effector functions is caused by post-translational prevention of signalling, which identifies novel molecular targets for immune monitoring and immune therapy of chronic hepatitis B.

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HBcore-specific CXCR6+CD8 T cells during persistent HBV replication in mice lose their effector function and have high CREM activity

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