VIRUS INDUCED DC MATURATION AND CELLULAR IMMUNITY

病毒与树突状细胞的相互作用被认为在决定是否产生保护性Th1反应或不太有效的Th2反应方面起着关键作用。我们的数据与DC必须达到最大成熟才能产生Th1免疫的假设一致。这种成熟可以通过与细菌、LPS、CpG、炎症细胞因子或病毒感染孵育DC来实现。我们有证据表明，活病毒诱导Th1细胞，而灭活病毒导致Th2细胞的扩增。因此，有证据强烈表明干扰素途径的元件在产生Th1免疫中的作用。例如，干扰素调节因子已被证明在IL-12的产生和对γ干扰素的反应中发挥作用，缺乏干扰素调节因子的小鼠无法产生有效的Th1反应。我们推测，与活病毒相比，灭活病毒无法激活导致DC成熟的干扰素途径，因此无法启动Th1免疫。特别是，我们建议研究干扰素病毒NS1突变体，因为有证据表明它们在激活干扰素途径方面比野生型病毒更有效，因此可能是DC成熟和Th1免疫的更有效诱导剂。我们还建议利用干扰素途径中不同元素基因缺陷小鼠的DC来更精确地定义与DC成熟相关的分子事件。最后，我们建议应用从早期实验中获得的信息来创建一个方案，使通常在灭活病毒中看到的Th2反应可以转化为Th1反应。应该强调的是，所获得的结果的重要性可能主要与流感病毒疫苗无关，但可能对认为有价值的Th1免疫反应的非复制疫苗具有重要意义。

The interaction of viruses with dendritic cells is believed to play a key role in determining whether protective Th1 responses or less effective Th2 responses are generated. Our data are consistent with the hypothesis that for DC to generate Th1 immunity they must achieved maximum maturation. Such maturation can be achieved by incubating DC with bacteria, LPS, CpG, inflammatory cytokines or by virus infection. We have evidence that whereas live virus induces Th1 cells, inactivated viral leads to expansion of Th2 cells. Accordingly, evidence strongly suggests a role for elements of the interferon pathway in generating Th1 immunity. For example, interferon regulatory factors have been shown to play a role in IL-12 production and responsiveness to gamma interferon and mice deficient in interferon regulatory factors are unable to generate effective Th1 responses. We speculate that in contrast to live virus, inactivated virus is unable to prime for Th1 immunity results from its failure to activate the interferon pathway leading to DC maturation. In particular, we propose to examine interferon virus NS1 mutants because evidence exists that they are even more effective than wild type virus in activating the interferon pathway and hence may be more potent inducers of DC maturation and Th1 immunity. We also propose to employ DC from mice genetically deficient in different elements of the interferon pathway to more precisely define the molecular events associated with DC maturation. Finally, we propose to apply information gained from earlier experiments to create a protocol whereby the Th2 response normally seen with inactivated virus can be converted to a Th1 response. It should be emphasized that the importance of the results obtained may not primarily bear on influenza virus vaccines but may have important implications for non-replicating vaccines where a Th1 immune response is deemed valuable.