DEREGULATED INTRACELLULAR PATHWAYS DEFINE NOVEL MOLECULAR TARGETS FOR HBV-SPECIFIC CD8 T CELL RECONSTITUTION IN CHRONIC HEPATITIS B

ABSTRACT: 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

ORGANISM(S): Homo sapiens

PROVIDER: GSE217838 | GEO | 2023/05/24

REPOSITORIES: GEO