Simultaneously boosting both humoral and cellular immunity following vaccination

描述（由申请人提供）：在本申请中，我们假设两个相互调节的转录因子Sox4和IRF4在决定小鼠和人类细胞毒性T淋巴细胞（CTL）反应的数量和质量方面发挥核心作用。此外，我们将验证CD4和CD8 T细胞中IRF4和Sox4之间失调的平衡（即IRF4减少和Sox4表达增强）会损害老年人Tfh和CTL反应的发展，从而导致流感疫苗接种后体液和细胞免疫的年龄相关缺陷。本应用程序的目的是剖析流感感染期间诱导有效的抗病毒CTL反应的分子机制，并使用免疫学和药理学工具同时增强细胞和体液免疫，以提高老年人流感疫苗的效力。提出了两个具体目标。目的：阐明流感感染过程中Sox4-IRF4通路控制抗病毒CTL反应的数量和质量的机制。目的2：确定PGE2/TGF-依赖性Sox4-IRF4调控在流感疫苗接种后体液和细胞免疫年龄相关缺陷中的T细胞内在作用。季节性流感每年在全球造成约50万人死亡，在美国造成多达5万人死亡，其中大多数死亡发生在老年人中。CD8 ctl是有效清除流感病毒感染所必需的，人类体内预先存在的CD8 ctl水平与预防有症状的大流行性流感密切相关。因此，了解在流感感染和免疫过程中调节CTL反应有效发展的转录程序具有设计未来流感治疗方法和改进流感疫苗设计的潜力。此外，预防流感的一个主要问题是，老年人对目前的流感疫苗反应不佳。因此，即使在流感疫苗接种率很高的人群中，流感感染导致的住院率在美国也高出10至30倍

DESCRIPTION (provided by applicant): In this application, we hypothesize that two reciprocally regulated transcriptional factors, Sox4 and IRF4, play a central role in determining the quantity and quality of both murine and human cytotoxic T lymphocyte (CTL) responses. In addition, we will test the hypothesis that the dysregulated balance between IRF4 and Sox4 (i.e. diminished IRF4 and enhanced Sox4 expression) in CD4 and CD8 T cells impairs the development of Tfh and CTL responses in aged individuals, thereby leading to the age-associated defects in both humoral and cellular immunity following influenza vaccination. The goals of this application are to dissect the molecular mechanisms by which effective anti-viral CTL responses are induced during influenza infection, and to use immunological and pharmacological tools to simultaneously boost cellular and humoral immunity to increase influenza vaccine efficacy in aged individuals. Two specific Aims are proposed. Aim1: To elucidate the mechanisms by which the Sox4-IRF4 circuit controls the quantity and quality of anti-viral CTL responses during influenza infection. Aim 2: To define the T cell intrinsic role of PGE2/TGF-�ependent Sox4-IRF4 regulation in age-associated defects in humoral and cellular immunity following influenza vaccination. Relevance statement Seasonal influenza kills ~500,000 people globally and up to 50,000 people in the United States each year, most of deaths occur in the elderly. CD8 CTLs are required for efficient clearance of influenza virus infection and the levels of pre-existing CD8 CTLs in humans tightly correlate with the protection against symptomatic pandemic influenza. Thus, understanding the transcriptional programs regulating the efficient development of CTL responses during influenza infection and immunization has the potential for designing future influenza therapeutics and for improving influenza vaccine design. In addition, a major problem in influenza prevention is that elderly adults respond poorly to current influenza vaccines. As a result, even in a population with a high rate of influenza vaccination, influenza infection causes 10- to 30- times more hospitalizations in the elderly annually compared to younger individuals. Therefore, the successful completion of this application will shed light on the molecular basis underlying the age-associated defects in both humoral and cellular immunity following influenza vaccination. Furthermore, we expect that this application will establish principles that could be utilized in the future to improve the effiacy of influenza and other pathogen vaccines in aged individuals.