Adaptive and Innate Immunity, Memory and Repertoire in Vaccination and Infection

描述（由申请人提供）：流感病毒及其变种在发展中国家和发达国家仍然是一个严重的公共卫生威胁，仅在美国平均每年就造成约35,000人死亡，数十万人住院。在斯坦福大学人类免疫学合作中心的更新申请中，我们希望利用我们在分析流感疫苗反应方面的丰富经验来解决一些关于人类免疫系统如何对流感疫苗接种或感染作出反应的基本问题和假设。我们也希望继续推进与分析人类免疫反应相关的免疫监测技术，如飞行时间细胞术，或CyTOF，组合肽- mhc四聚体，新的TCR和BCR库和基因表达分析方法，开辟全新的研究领域和检验假设的方法。我们提案的总体主题是解决关于人类免疫系统如何在幼儿、青少年和年轻人中发展和变化的具体问题。虽然在监测婴儿和幼儿的免疫反应方面存在相当大的挑战，但新技术，其中许多是在斯坦福大学开发的，现在使一些非常基本的问题变得可行。这些包括测试关于记忆表型T细胞，流感特异性效应和记忆CD4+ T细胞（PI）的假设，先天免疫因子和CD4+ T细胞对新型离体系统中流感病毒感染的影响（P2），免疫球蛋白，T细胞受体和NK库在不同年龄组对疫苗接种的反应中的发展（P3），以及提高CyTOF仪器的能力（P4）。这些努力将得到我们的行政(A)、试点(B)、临床(C)、人类免疫监测(D)、基因组学(E)和生物信息学(F)核心的有力支持。这些核心中的大多数已经存在了四年或更长时间，并为该小组的研究活动提供了至关重要和最先进的支持。我们正在进入人类免疫学的一个激动人心的时期，我们认为斯坦福大学的团队将继续非常富有成效。

DESCRIPTION (provided by applicant): The influenza virus and its variants remains a serious public health threat in both developing and developed counties, accounting for ~35,000 deaths and hundreds of thousands hospitalized in the US alone in an average year. In this renewal application from the Cooperative Center for Human Immunology at Stanford University, we wish to leverage our considerable experience in analyzing the influenza vaccine response to address some fundamental questions and hypotheses regarding how the human immune system responds to influenza vaccination or infection. We also wish to continue advancing immune monitoring technologies relevant to analyzing the human immune response, such Cytometry by Time-Of-Flight, or CyTOF, combinatorial peptide-MHC tetramers and new TCR and BCR repertoire and gene expression analysis methods that open up entirely new areas of investigation and ways to test hypotheses. The general theme of our proposal is to address specific questions regarding how the human immune system develops and changes in young children, adolescents and young adults. While there are considerable challenges in monitoring the immune responses of infants and young children, new technologies, many of them developed here at Stanford, now make some very fundamental questions feasible to address. These include testing hypotheses about memory phenotype T cells, and of flu-specific effector and memory CD4+ T cells (PI), the influence of innate immune factors and CD4+ T cells on influenza virus infection in a novel ex vivo system (P2), the development of the immunoglobulin, T cell receptor and NK repertoires in response to vaccination in different age groups from our twin cohort (P3), and advancing the capabilities of the CyTOF instrument (P4). These efforts will be very ably supported by our Administrative (A), Pilot (B), Clinical (C), Human Immune Monitoring (D), Genomics (E) and Bioinformatics (F) Cores. Most of these cores have been in place for four or more years and have provided vital and state-of the-art support for the research activities of the group. We are entering into an exciting period of time for human immunology and we think that the Stanford team will continue to be extremely productive.