Human CD8+ and CD4+ T Cells Responses to Influenza Infection and Vaccination

该项目的总体目标是确定人类T细胞对流感感染的反应，并 年轻人和老年人的三价灭活流感疫苗(TIV)。我们假设(1)人类T细胞 年轻人对疫苗接种和感染的细胞反应将比老年人更大， (2)人类CD4+和CD8+T细胞对疫苗的应答将低于对感染的应答；(3)TLV诱导的 T细胞反应将与个别获得许可的疫苗中的内部蛋白质数量相关。 甲型流感病毒血凝素(HA)是保护性中和抗体的靶点，这种抗体具有亚型特异性 并且容易受到抗原漂移的影响。CD4+和CD8+T细胞反应被认为是更多的亚型 交叉反应。在甲型流感病毒感染小鼠模型上的研究清楚地表明，T细胞可以 提供第二条重要的防线，特别是在面对显著的抗原漂移或由于 病毒的出现与HA抗体结合部位的变化有关，临床研究也有限 这表明了T细胞对保护的重要性，特别是在高危老年人口中。的确有, 然而，只有有限数量的关于人类T细胞对流感感染或 接种疫苗。重要的是，甲型流感病毒T细胞之间似乎有更多的亚型交叉反应 抗原表位比HA上的抗体表位高。目前，有限的数据表明，目前的TIV导致低 以调节CD4+和CD8+T细胞的反应。然而，我们发现了一些具有高T细胞的个体 对TIV的反应。最近，我们和另一个小组也发现了流感内部蛋白质的数量 TIV有所不同。尽管美国每年推荐和使用约1亿剂疫苗 单独来说，对TIV诱导T细胞反应的了解很少，对它们的研究也一无所知 对疫苗相关保护的贡献。在目标1中，我们建议分析CD4+和CD8+T细胞 年轻人和老年人对TIV疫苗接种的反应。在这些研究中，我们还将比较这三个 美国许可的TIV具有刺激CD4+和CD8+T细胞反应和保护的能力(在老年人中 成人)。在目标2中，我们建议表征CD4+和CD8+T细胞对自然流感感染的反应 并将其与TIV诱导的CD4+和CD8+T细胞反应进行比较。 这些分析可能会导致改进流感疫苗的方法，这种疫苗可以预防 新出现的流感病毒感染，包括H5N1和其他非人类毒株。

The overall goal of this project is to define the human T cell responses to influenza infection and to trivalent inactivated influenza vaccines (TIV) in younger and older adults. We hypothesize that (1) human T cell responses in younger adults will be greater than those in older adults to vaccination and to infection, (2) human CD4+ and CD8+ T cell responses will be lower to vaccine than to infection and (3) the TlV-induced T cell responses will correlate with the amount of internal proteins in the individual licensed vaccines. Influenza A virus hemagglutinin (HA) is a target of protective neutralizing antibodies, which are subtypespecific and vulnerable to antigenic drift. CD4+ and CD8+ T cell responses are thought to be more subtype cross-reactive. It is clear from studies in mouse models of influenza A virus infections that T cells can provide a second important line of defense, especially in the face of marked antigenic drift or shift due to emergence of viruses with changes in HA antibody combining sites, and there are also limited clinical studies which suggest the importance of T cells for protection, especially in a high-risk elderly population. There is, however, only a limited amount of data available on human T cell responses to influenza infection or vaccination. Importantly there appears to be more subtype cross-reactivity among influenza A virus T cell epitopes than to the antibody epitopes on HA. At present limited data suggest that current TIVs induce low to moderate CD4+ and CD8+ T cell responses. However, we found some individuals with high T cell responses to TIV. Recently, we and the other group also found the amount of influenza internal proteins in the TIVs differs. Despite the recommendation and use of about 100 million vaccine doses per year in the US alone, very little is known about TIVs induction of T cell responses and nothing is known about their contribution to vaccine associated protection. In Aim 1 we propose to analyze CD4+ and CD8+ T cell responses to TIV vaccination in younger and older adults. In these studies, we will also compare the three US-licensed TIVs for their ability to stimulate CD4+ and CD8+ T cell responses and for protection (in older adults). In Aim 2 we propose to characterize CD4+ and CD8+ T cell responses to natural influenza infections in younger and older adults and compare them to the CD4+ and CD8+ T cell responses induced by TIV. These analyses may lead to approaches towards improved influenza vaccines, which can protect against new and emerging influenza virus infections including H5N1 and other non-human strains.