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Transcriptome profile of HBV-specific CD8 cells from acute, resolved and chronic patients

ABSTRACT: HBV-specific CD8 cells are deeply exhausted in chronic hepatitis B and their function can only be partially corrected by modulation of up-regulated inhibitory pathways, suggesting a more complex molecular interplay. With the aim of identifying more suitable molecular targets to correct T cell dysfunction, we compared the transcriptome profile of HBV-specific CD8 cells of acute and chronic patients with the reference profile of HBV- and Flu-specific CD8 cells from patients able to resolve HBV infection spontaneously and from healthy subjects. The results indicate that exhausted HBV-specific CD8 cells are deeply impaired at a metabolic and energetic level with a prevalent down-regulation of different key cellular processes centered on an extensive alteration of mitocondrial functions. Mitochondrial modulation by antioxidant compounds could improve significantly the HBV-specific T cell function with minimal effect on T cells of different specificity. The results identify mitochondria as ideal targets for functional T cell reconstitution strategies to cure HBV infection

ORGANISM(S): Homo sapiens

PROVIDER: GSE67801 | GEO | 2017/01/11

SECONDARY ACCESSION(S): PRJNA280961

REPOSITORIES: GEO

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Project description:HCV-specific CD8 cells are deeply exhausted in chronic hepatitis C and their function can only be partially corrected by modulation of up-regulated inhibitory pathways, suggesting a more complex molecular interplay. With the aim of identifying more suitable molecular targets to correct T cell dysfunction, we compared the transcriptome profile of HCV-specific CD8 cells of acute and chronic patients with the reference profile of HCV- and Flu-specific CD8 cells from patients able to resolve HBV infection spontaneously and from healthy subjects. First, the gene-expression profile of HCV-specific CD8 T cells from patients with chronically-evolving acute infection, that correspond to early but not established T exhausted cells, is consistent with a substantial functional impairment at the energetic and metabolic levels that leads to the accumulation of reactive oxygen species that contributes to the activation of stress sensor signaling pathways. A specific inhibition of the hyperactivated signaling downstream effectors elicits a functional metabolic T cell reconstitution in the majority of the tested patients early during HCV infection. Second, a predominant feature of late exhausted HCV specific T cells is a global downregulation of gene expression that affects multiple core processes, ranging from proteasome-dependent protein turnover to DNA repair, transcription, metabolism and cell cycle, that is presumably a consequence of precocious and dysregulated activity of histone methyltransferases (e.g. G9a and EZH2 HMTs). Third, a functional inhibition of HMTs leads to a T cell function reconstitution both as anti-viral cytokine production and as proliferative capacity and to a metabolic restoration specifically for late exhausted CD8 T cells with a strongly preferential effect on HCV-specific T cells. Virus-specific CD8+ T cells were isolated and sorted from early acute self-limited (5 patients), early chronic (8 patients), late resolved (4 patients), late chronic (7 patients) and from five healthy donors. RNA from sorted CD8+ T cells was processed, amplified, labeled, and hybridized to Agilent microarrays.

Project description:Background and aims: In chronic HBV infection elevated ROS levels by dysfunctional mitochondria can cause increased protein oxidation, proteostasis engulfment and DNA damage in exhausted virus-specific CD8 T cells. Aim of this study was to understand how these defects are mechanistically interconnected, to further elucidate T cell exhaustion pathogenesis and to design novel T cell-based therapies. Methods: DNA damage and DNA repair mechanisms, including parylation, CD38 expression, histone acetylation and telomere length were studied by flow cytometry in dextramer-stained HBV-specific CD8 T cells from chronic HBV patients. FLU-specific CD8 cells from the same patients and healthy subjects served as controls. Correction of intracellular signaling alterations and improvement of anti-viral T cell functions by the NAD precursor NMN and by CD38 inhibition, was assessed by fluorescent probes and antibodies in flow cytometry Results: Elevated DNA damage was associated with defective DNA repair processes, including NAD-dependent parylation, in HBV-specific CD8 cells of chronic HBV patients. NAD depletion in these patients was indicated by the overexpression of CD38, the major NAD consumer, and by the significant improvement of DNA repair mechanisms, mitochondrial and proteostasis functions and epigenetic regulation by NAD supplementation, which could also improve the overall HBV-specific antiviral CD8 T cell function. Conclusions: Our study delineates a model of CD8 T cell exhaustion whereby multiple functionally interconnected intracellular defects, including telomere shortening, are causally related to NAD depletion suggesting similarities between T cell exhaustion and cell senescence. Correction of these deregulated intracellular functions by NAD supplementation can also restore anti-viral CD8 T cell activity and thus represents a promising potential therapeutic strategy for chronic HBV infection. Gene expression profiling analysis using data derived from low input RNA-seq of patients' virus-specific CD8 T cells either upon in vitro culture or ex-vivo isolated from total PBMCs

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Transcriptome profile of HBV-specific CD8 cells from acute, resolved and chronic patients

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