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The activation of the interferon (IFN) system, which is triggered largely by the recognition of viral nucleic acids, is one of the most important host defense reactions against viral infections. Although influenza A and B viruses, which both have segmented negative-strand RNA genomes, share major structural similarities, they have evolutionarily diverged, with total genetic incompatibility. Here we compare antiviral-inducing mechanisms during infections with type A and B influenza viruses in human dendritic cells. We observed that IFN responses are induced significantly faster in cells infected with influenza B virus than in cells infected with type A influenza virus and that the early induction of antiviral gene expression is mediated by the activation of the transcription factor IFN regulatory factor 3 (IRF3). We further demonstrate that influenza A virus infection activates IFN responses only after viral RNA (vRNA) synthesis, whereas influenza B virus induces IFN responses even if its infectivity is destroyed by UV treatment. Thus, initial viral transcription, replication, and viral protein synthesis are dispensable for influenza B virus-induced antiviral responses. Moreover, vRNA molecules from both type A and B viruses are equally potent activators of IFN induction, but incoming influenza B virus structures are recognized directly in the cytosol, while influenza A virus is able to evade early recognition. Collectively, our data provide new evidence of a novel antiviral evasion strategy for influenza A virus without a contribution of the viral NS1 protein, and this opens up new insights into different influenza virus pathogenicities. [ABSTRACT FROM AUTHOR]

The clinical picture of influenza may vary from mild respiratory infection to pneumonia requiring intensive care. Annual epidemics are most commonly caused by H3N2 or H1N1 type influenza A or influenza B viruses. The population's immune protection against a new virus type is low, whereupon morbidity and mortality may be high. Vaccinations are the most important means to decrease influenza morbidity. Annual variation and quick intercontinental migration of influenza viruses, combined with the possibility of the creation of reassortant viruses, are significant challenges for the development of influenza vaccines.

Interleukin (IL)-21 is a T cell-derived cytokine that regulates innate and adaptive immune responses. IL-21 receptor (IL-21R), which is expressed in natural killer (NK) and T cells, is structurally homologous to IL-2Rbeta and IL-15Ralpha. These receptors also share a common cytokine receptor gamma-chain with IL-4, IL-7, and IL-9. Macrophage- or dendritic cell-derived interferon (IFN)-alpha/beta is a key cytokine in regulation of NK and T cell functions. We demonstrate here that in addition to activating IFN-gamma gene expression, IFN-alpha/beta and IL-12 enhance the mRNA expression of IL-21 in activated human T cells. In addition, IFN-alpha/beta enhanced T cell receptor stimulation-induced IL-21 and IFN-gamma gene expression in resting T cells. The promoter analysis of IL-21 gene revealed a putative IFN-gamma activation site element, which was found to bind signal transducer and activator of transcription 1 (STAT1), STAT2, STAT3, and STAT4 proteins in IFN-alpha/beta-stimulated NK or T cell extracts. In contrast to IL-21 expression, IFN-alpha/beta down-regulated IL-21R mRNA expression in NK and T cells. IFN-alpha/beta-induced down-regulation of IL-21R expression resulted in reduced STAT3 phosphorylation and DNA binding after IL-21 stimulation. In conclusion, our results suggest a novel role for IFN-alpha/beta in the regulation of IL-21 response.

NK and T cell-derived IFN-gamma is a key cytokine that stimulates innate immune responses and directs adaptive T cell response toward Th1 type. IL-15, IL-18, and IL-21 have significant roles as activators of NK and T cell functions. We have previously shown that IL-15 and IL-21 induce the expression of IFN-gamma, T-bet, IL-12R beta 2, and IL-18R genes both in NK and T cells. Now we have studied the effect of IL-15, IL-18, and IL-21 on IFN-gamma gene expression in more detail in human NK and T cells. IL-15 clearly activated IFN-gamma mRNA expression and protein production in both cell types. IL-18 and IL-21 enhanced IL-15-induced IFN-gamma gene expression. IL-18 or IL-21 alone induced a modest expression of the IFN-gamma gene but a combination of IL-21 and IL-18 efficiently up-regulated IFN-gamma production. We also show that IL-15 activated the binding of STAT1, STAT3, STAT4, and STAT5 to the regulatory sites of the IFN-gamma gene. Similarly, IL-21 induced the binding of STAT1, STAT3, and STAT4 to these elements. IL-15- and IL-21-induced STAT1 and STAT4 activation was verified by immunoprecipitation with anti-phosphotyrosine Abs followed by Western blotting with anti-STAT1 and anti-STAT4 Abs. IL-18 was not able to induce the binding of STATs to IFN-gamma gene regulatory sites. IL-18, however, activated the binding of NF-kappa B to the IFN-gamma promoter NF-kappa B site. Our results suggest that both IL-15 and IL-21 have an important role in activating the NK cell-associated innate immune response.