Regulation of Humoral Immunity to Influenza Virus

描述(申请人提供)：仅在美国，流感病毒感染每年造成多达40,000人死亡。当预先存在的免疫不存在时，这种病毒可能会通过新的重组体导致更致命的大流行。B细胞对流感病毒的体液反应构成了免疫介导的短期和长期保护的主要组成部分。我们关于B细胞反应调节的大部分知识来自体内和体外对抗蛋白或半抗原载体注射的分析。然而，越来越多的证据表明，B细胞立即早期接触感染诱导的先天信号塑造了B细胞的反应，这在一定程度上是由在这笔赠款的初始资助期进行的研究提供的。人们对这些信号的性质以及它们影响B细胞反应的机制知之甚少。这里要检验的工作假设是，感染诱导的局部先天免疫信号对参与诱导对流感病毒感染的保护性免疫的各种B细胞亚群进行不同的调节。这些研究的长期目标是确定对病毒感染的呼吸道免疫是如何诱导和调节的。这项建议的目的是确定先天免疫信号，特别是I型干扰素影响抗病毒B细胞反应的质量和大小的机制。这是基于上一次资助期间的研究，这些研究表明I型干扰素是感染后2天内区域淋巴结中主要的感染诱导B细胞刺激因素。为了实现我们的目标，我们将实现三个具体目标。具体目标#1将确定B细胞收到的直接IFNR信号影响单个B细胞对流感的反应成分的大小和保护能力的机制：B-1细胞、滤泡外病灶和生发中心反应。具体目标#2将确定Toll样受体(TLR)3和7介导的信号在抗病毒B细胞对流感感染的反应调节中的作用，以及它们与B细胞受体和/或T细胞帮助提供的刺激的整合。在特定的目标#3中，将研究IFNR介导的B细胞刺激对局部CD4T细胞对流感病毒感染的反应的影响，特别是对CD40-CD40L介导的Help的影响。体外和体内测试是通过使用病毒特异性T细胞受体转基因小鼠来辅助的。这些研究的完成将有助于更好地了解调节诱导抗病毒B细胞对流感病毒的保护性反应的过程。

DESCRIPTION (provided by applicant): Influenza virus infections contribute yearly up to 40,000 human deaths in the U.S. alone. This virus could cause much more deadly pandemics through novel reassortants when pre-existing immunity does not exists. Humoral responses to influenza virus contributed by B cells form a major component of immune-mediated short and long-term protection. Much of our knowledge regarding the regulation of B cell responses comes from in vivo and in vitro analyses of anti-protein or hapten-carrier injections. However, increasing evidence, provided in part by studies conducted during the initial funding period of this grant, suggests that immediate early exposure of B cells to infection-induced innate signals shape the responses of B cells. Little is known about the nature of these signals and the mechanisms by which they affect the B cell response. The working hypothesis to be tested here is that infection-induced local innate immune signals differentially regulate various B cell subsets involved in the induction of protective immunity to influenza virus infection. The long-term objective of the studies is to determine how respiratory tract immunity to viral infections is induced and regulated. The objective of this proposal is to determine the mechanisms by which innate immune signals, particularly type I IFN shape the quality and magnitude of antiviral B cell responses. This is based on studies during the last funding period which showed type I IFN as a major infection-induced B cell stimulus in regional lymph nodes within 2 days of infection. To achieve our objective three Specific Aims will be carried out. Specific Aim #1 will determine the mechanisms by which direct IFNR-signals received by B cells affect the magnitude and protective capacity of individual B cell response components to influenza: B-1 cells, extrafollicular foci and germinal center responses. Specific Aim #2 will determine the role of toll-like receptor (TLR) 3 and 7-mediated signals on antiviral B cell response regulation to influenza infection and their integration with stimuli provided by the B cell receptor and/or T cell help. In Specific Aim #3 the effects of IFNR-mediated B cell stimulation on local CD4 T cell responses to influenza virus infection and particular the affects on CD40-CD40L mediated help will be investigated. In vitro and in vivo tests are aided by the use of virus-specific T cell receptor transgenic mice. Completion of these studies will contribute to a better understanding of the processes that regulate the induction of protective antiviral B cell responses to influenza virus.