Maintaining Robust T Cell Immunity For Broad Protection Against Influenza

摘要：保持强大的T细胞免疫力以广泛预防流感 目前使用的流感疫苗被设计为主要产生针对外壳蛋白的中和抗体， 必须每年重新制定和提供。他们只是部分有效，而活感染赋予高度 保护性T细胞介导的免疫提供了多种额外的保护机制，也是至关重要的 用于产生持久的中和Ab。 我们最近的研究表明，保护性CD4 T细胞免疫的产生需要强的病毒介导。 抗原和感染介导的信号持续至少一周。这是因为效应器需要接收 这些信号在一个明确的检查点，以完成其过渡到内存。目前的疫苗很少供应 Ag或相关病原体识别信号（PRS）在最佳水平这么长时间。此外，人类 应答通常依赖于已经产生的记忆T细胞，并且不知道记忆CD4 T细胞是否 必须经过类似的检查点以重新生成辅助（20）存储器响应。 在这里，我们将比较由灭活的全流感病毒产生的记忆性CD4 T细胞的体内应答， 疫苗与活感染，并确定20个CD4效应子是否也需要抗原和病原体信号。 类似的“效应物检查点”，通过类似的机制，以重新生成20个CD4记忆，并且如果这种记忆 确实提供了针对多种甲型流感病毒的强异亚型保护。 如果是这样的话，应该有可能增加疫苗，以提供抗原和病原体的信号，无论是在最初和在 这应该为新一代更有效的流感疫苗建立一个框架 具有更广泛的保护作用，并提供持久的免疫力。此外，同样的策略很可能 可以应用于其他病原体的疫苗。

ABSTRACT: Maintaining Robust T Cell Immunity for Broad Protection Against Influenza Influenza vaccines currently in use are designed, primarily to produce neutralizing antibody to coat proteins and must be reformulated and given each year. They are only partially effective, while live infection confers highly protective T cell mediated immunity which provides multiple additional protective mechanisms and also is crucial for generation of long-lasting neutralizing Ab. Our recent studies indicate that generation of protective CD4 T cell immunity requires strong presentation of viral antigen and infection-mediated signals lasting at least a week. This is because the effectors need to receive these signals during a clear-cut checkpoint to complete their transition to memory. Current vaccines rarely supply Ag or the relevant pathogen-recognition signals (PRS) at optimal levels for this long. Moreover, human responses often depend on already generated memory T cells, and it is not known whether memory CD4 T cells must go through a similar checkpoint to re-generate secondary (20) memory responses. Here we will compare the in vivo 20 response of memory CD4 T cells generated by inactivated whole influenza vaccine vs. live infection and determine whether the 20 CD4 effectors also need Ag and pathogen signals at a comparable “effector checkpoint”, via similar mechanisms, to re-generate 20 CD4 memory and if such memory does indeed provide strong heterosubtypic protection against multiple influenza A viruses. If so, it should be possible to augment vaccines to provide the Ag and pathogen signals both initially and at the checkpoint, and this should create a framework for a new generation of more effective vaccines against influenza that are more broadly protective and give long-lasting immunity. Moreover, it is likely that the same strategies could be applied to vaccines against other pathogens.