VIRUS INDUCED DC MATURATION AND CELLULAR IMMUNITY

病毒与树突状细胞的相互作用被认为在确定是否产生保护性Th 1应答或不太有效的Th 2应答中起关键作用。我们的数据是一致的假设，DC产生Th 1免疫，他们必须达到最大的成熟。这种成熟可以通过将DC与细菌、LPS、CpG、炎性细胞因子一起孵育或通过病毒感染来实现。我们有证据表明，虽然活病毒诱导Th 1细胞，灭活病毒导致Th 2细胞的扩增。因此，证据强烈表明干扰素途径的元件在产生Th 1免疫中的作用。例如，干扰素调节因子已显示在IL-12产生和对γ干扰素的应答中起作用，并且干扰素调节因子缺陷的小鼠不能产生有效的Th 1应答。我们推测，与活病毒相反，灭活病毒不能引发Th 1免疫，这是由于其未能激活导致DC成熟的干扰素途径。特别是，我们建议研究干扰素病毒NS 1突变体，因为有证据表明，它们在激活干扰素途径方面甚至比野生型病毒更有效，因此可能是DC成熟和Th 1免疫的更有效诱导剂。我们还建议使用来自在干扰素途径的不同元件中遗传缺陷的小鼠的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，以创建一个协议，使通常看到的灭活病毒的Th 2反应可以转换为Th 1反应。应该强调的是，所获得的结果的重要性可能并不主要影响流感病毒疫苗，但可能对Th 1免疫应答被认为是有价值的非复制型疫苗具有重要意义。

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.