Mechanisms of protection by CD4 cells against influenza

描述（由申请方提供）：流感感染仍然是导致发病率和死亡率的主要健康问题，尤其是在老年人群中。目前的疫苗依赖于诱导针对外壳蛋白的中和抗体;然而，这些疫苗对血清学上不同的病毒株无效。因此，开发诱导细胞免疫的疫苗也很重要。虽然CD 8细胞毒性T细胞已被证明在控制流感病毒感染中是重要的，但CD 4 T细胞在病毒清除和保护中也起着不可或缺的作用，特别是在缺乏CD 8 T细胞的情况下。CD 4 T细胞促进病毒清除和保护的机制仍然知之甚少;然而，IFN-γ似乎是CD 4对流感反应的重要组成部分。例如，产生IFN-γ的CD 4 T细胞效应器可以防止致命的流感感染，而缺乏这种细胞因子的细胞则不能提供保护。在急性感染期间，IFN-γ的产生似乎与细胞分裂有关，其中气道中的流感特异性CD 4细胞仅在大于6次细胞分裂后表达大量的该细胞因子。该提案将研究CD 4 T细胞产生IFN-γ的能力与保护小鼠免受致命流感感染的能力之间的关系。目标1将使用体外和体内方案来产生基于IFN-γ产生的处于不同分化阶段的CD 4效应物。然后分析这些效应物迁移到肺并提供保护的能力。目的2将研究IFN-γ在流感感染期间CD 4依赖性生存中的作用。

DESCRIPTION (provided by applicant): Influenza infection remains a major health concern causing morbidity and mortality, especially in elderly populations. Current vaccines rely on inducing neutralizing antibodies to coat proteins; however, these vaccines are ineffective against serologically distinct viral strains. Therefore, it is important to develop vaccines that induce cellular immunity as well. Although CD8 cytotoxic T cells have been shown to be important in controlling influenza viral infections, CD4 T cells also play an integral role in viral clearance and protection, especially in the absence of CD8 T cells. The mechanisms by which CD4 T cells promote viral clearance and protection remain poorly understood; however, IFN-gamma appears to be an important component of the CD4 response to influenza. For example, CD4 T cell effectors that produce IFN-gamma can protect against lethal influenza infection while cells deficient in this cytokine do not protect. During acute infection, the production of IFN-gamma appears linked to cell division with influenza specific CD4 cells in the airways expressing high amounts of this cytokine only after greater than six cell division. This proposal will examine the relationship between the ability of CD4 T cells to produce IFN-y and the ability to protect mice against lethal influenza infection. Aim 1 will use in vitro and in vivo protocols to generate CD4 effectors that are at distinct stages of differentiation based on IFN-gamma production. These effectors will then be analyzed for their ability to migrate to the lung and confer protection. Aim 2 will investigate the role of IFN-gamma in CD4 dependent survival during; influenza infection.