Regulation of Humoral Immunity to Influenza Virus

部分是通过在本项目最初的资助期内进行的研究 Grant认为，B细胞早期接触感染诱导的先天细胞 信号会影响B细胞的反应。人们对这些疾病的本质知之甚少 信号及其影响B细胞反应的机制。在工作中 这里要检验的假设是感染诱导的局部先天免疫信号 差异性调控参与保护性免疫诱导的各种B细胞亚群 对流感病毒感染的免疫力。这项研究的长远目标是 确定呼吸道对病毒感染的免疫力是如何诱导和调节的。这个 这项建议的目的是确定先天免疫的机制 信号，特别是I型干扰素影响抗病毒B细胞的质量和大小 回应。这是基于上一次资助期的研究，研究表明第一类 干扰素作为感染后2天内区域淋巴结内主要的B细胞刺激因子 感染。为了实现我们的目标，我们将实现三个具体目标。特定目标 #1将确定由B细胞接收的直接IFNR信号的机制 影响单个B细胞反应成分的大小和保护能力 流感：B-1细胞、毛囊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上的作用 细胞对流感感染的反应调节及其与刺激的整合 受B细胞受体和/或T细胞的帮助。在特定目标#3中，IFNR介导的效果 B细胞刺激局部CD4T细胞对流感病毒感染的反应及特异性 将研究其对CD40-CD40L介导的HELP的影响。体外和体内试验 都是通过使用病毒特异性T细胞受体转基因小鼠来辅助的。完成 这些研究将有助于更好地理解调节 诱导对流感病毒的保护性抗病毒B细胞反应。 项目说明第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