Molecular Mechanisms Of Viral Immune Escape And Anti-viral Response

CD4~+ T cells with cytotoxic potential are specifically induced at the site of infection during influenza virus infection. The development of CD4~+ T cells with cytotoxic potential in vivo was dependent on the cooperation of the STAT2-dependent type I interferon signaling and the interleukin-2/interleukin-2 receptor alpha pathway for the induction of the transcription factors T-bet and Blimp-1. We showed that Blimp-1 promoted the binding of T-bet to the promoters of cytolytic genes in CD4~+ T cells and was required for the cytolytic function of the in vitro- and in vivo-generated CD4~+ T cells with cytotoxic potential. Thus, our data define the molecular basis of regulation of the in vivo development of this functionally cytotoxic Th subset during acute respiratory virus infection(1).We compared the specific humoral and cellular immune responses among adults receiving monovalent pH1N1 flu vaccine to pH1N1 flu patients, close contacts of patients or healthy controls, and found that pH1N1 virus infection induced stronger virus-specific cellular and humoral immune responses than conventional vaccination. There were no differences in the specific anti-virus IgG titers between the flu vaccinated group and the non-immunized healthy controls, associated with failure to induce cellular immune responses. One year after the 2009 H1N1 pandemic, almost 70% of healthy controls developed asymptomatic or mild infections(101).B7-H1, an important co-inhibitory molecule of B7 family, can induce hepatocytic CD8+ T cells apoptosis. We found that IFN-γ and TNF-α can synergistically induce the expression of B7-H1 in hepatocytes. IFN-γ plays an important role whereas TNF-α has an auxiliary one. IFN-γ but not TNF-α can induce the expression of B7-H. Both of them cannot synergistically induce the activities of STAT1 and NF-κB. However, the induction of STAT1 and NF-κB is necessary for the expression of B7-H1 induced by IFN-γ and TNF-α. We also found that IFN-γ and TNF-α can synergistically induce the expression of IRF-1 in hepatocytes and the induction of STAT1 and NF-κB is required in this process. The expression of B7-H1 is IRF-1-dependent. So the synergistic induction of IRF-1 was the major reason for the induction of B7-H1 induced by IFN-γ and TNF-α synergistically. We also found that HBx can enhance the expression of B7-H1 and IRF-1 induced both by IFN-γ alone and by IFN-γ and TNF-α together. Exploring the crosstalk between NF-κB and STAT1 or NF-κB and IRF-1, might explain why IFN-γ and TNF-α can synergistically induce the expression of B7-H1 and why HBx can enhance the expression of B7-H1 in hepatocytes. We hope that our future work will shed light on the mechanisms of viral immune escape induced by IFN-γ and TNF-α synergistically and will bring more evidence for the role of HBx in this process.