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Abstract
Hepatitis B virus–specific (HBV-specific) CD8+ T cells fail to acquire effector functions after priming in the liver, but the molecular basis for the dysfunction is poorly understood. By comparing the gene expression profile of intrahepatically primed, dysfunctional HBV-specific CD8+ T cells with that of systemically primed, functional effector counterparts, we found that the expression of interferon-stimulated genes (ISGs) is selectively suppressed in the dysfunctional CD8+ T cells. The ISG suppression was associated with impaired phosphorylation of STAT1 in response to IFN-α treatment. Importantly, a strong induction of type I interferons (IFN-Is) in the liver facilitated the functional differentiation of intrahepatically primed HBV-specific CD8+ T cells in association with the restoration of ISGs’ expression in the T cells. These results suggest that intrahepatic priming suppresses IFN-I signaling in CD8+ T cells, which may contribute to the dysfunction. The data also suggest a therapeutic value of the robust induction of intrahepatic IFN-Is for the treatment of chronic HBV infection.
Highlights
CD8+ T cell responses play an essential role in terminating viral infections
To investigate molecular pathways correlated with Hepatitis B virus (HBV)-specific T cell dysfunction after priming in the liver, we compared the gene expression profiles between tolerant and effector HBV-specific CD8+ T cells
Adoptively transferred COR93-specific CD8+ T cells were purified from intrahepatic lymphocytes (IHLs) of HBV-Tg mice and splenocytes of immunized B6 mice
Summary
CD8+ T cell responses play an essential role in terminating viral infections. During persistent infections, virus-specific CD8+ T cells progressively lose functionality due to continuous antigen exposure [1]. Studies that examined transcriptional signatures of T cells revealed significant differences between effector, memory, and exhausted T cells in the expression of various molecules, such as inhibitory and costimulatory receptors, transcription factors, and signaling molecules [1, 3]. These pioneering studies have established a notion that exhausted T cells acquire a unique differentiation state, underlying mechanisms for T cell dysfunction likely differ between systemic and local infections because the nature of antigen-presenting cells is very different. DNA and RNA viruses probably create a very different immunological milieu for T cells
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