Regulation of Humoral Immunity to Influenza Virus

部分原因是在本项目最初供资期间进行的研究， 格兰特的研究表明，B细胞在感染诱导的先天性 信号塑造B细胞的反应。关于这些的性质知之甚少 信号及其影响B细胞应答的机制。工作 这里要检验的假设是，感染诱导的局部先天免疫信号 差异调节各种B细胞亚群参与诱导保护性 对流感病毒感染免疫。研究的长期目标是 确定呼吸道对病毒感染的免疫是如何诱导和调节的。的 这项建议的目的是确定先天免疫的机制， 信号，特别是I型干扰素塑造抗病毒B细胞的质量和数量 应答这是基于上一个供资期间的研究， IFN作为局部淋巴结中主要感染诱导的B细胞刺激物在感染后2天内 感染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将确定由B细胞接收的直接IFNR信号的机制 影响单个B细胞应答组分的大小和保护能力， 流感：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介导的信号对抗病毒B的作用 细胞对流感感染的应答调节及其与提供的刺激的整合 通过B细胞受体和/或T细胞的帮助。在具体目标#3中，IFNR介导的 B细胞刺激对局部CD 4 T细胞对流感病毒感染应答的影响 将研究对CD 40-CD 40 L介导的帮助的影响。体外和体内测试 通过使用病毒特异性T细胞受体转基因小鼠来辅助。完成 这些研究将有助于更好地了解调节 诱导针对流感病毒保护性抗病毒B细胞应答。 项目描述第6页

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. Project Description Page 6