Development of Antigen-specific B Cell Memory

描述(由申请人提供)：概述：当今使用的最有效的疫苗产生保护性的抗原特异性B细胞记忆。为了有效，记忆B细胞必须靶向正确的特异性，具有足够高的亲和力，并表达适当的抗体类别，为宿主提供长期的免疫保护。在体内，抗原特异性B细胞记忆的这三个基本属性在滤泡辅助性T细胞(TFH)的同源引导下逐渐出现。虽然我们对循环抗体了解很多，但对高亲和力类特异性记忆B细胞的发展仍然知之甚少，最终在体内提供B细胞介导的免疫保护。我们的长期目标是解开细胞程序和分子机制，这些细胞程序和分子机制在体内调节抗原特异性B细胞记忆的逐步发展。研究焦点：高亲和力抗原特异性抗体的产生是靶向抗原清除的一种强有力的手段，被认为是当今使用的所有疫苗的主要作用机制。当暴露于外来抗原时，单个辅助性T(TH)细胞和B细胞根据其所表达的抗原受体的个体特异性被招募到免疫反应中。接下来是一系列抗原特异性编程、功能分化和发育重新编程，以产生类别切换、高亲和力的记忆B细胞的方式，将在当前的研究提案中进行机械检查。具体目标：我们将使用小鼠蛋白疫苗模型来评估伴随着抗原特异性记忆B细胞逐步发育而来的转录编程的变化。我们认为，在发育的不同阶段，特定B细胞对抗原的识别启动了可分离的转录程序，介导与抗原特异性TFH细胞的生产性接触，并传播有效的B细胞记忆。在这里，我们将测试这一中心假说的多个方面，特别关注早期生发中心亲和力成熟的调节。 (SA-1)、抗原召回后的克隆进化(SA-2)和抗体类别的编程和维持(SA-3)是抗原特异性B细胞记忆的三个定义属性。我们的研究试图揭示B细胞记忆骨髓发育的内在机制，从而定义独特的靶点和新的策略，以增强未来疫苗和靶向免疫疗法的作用和效果。

DESCRIPTION (provided by applicant): Overview: Most effective vaccines in use today generate protective antigen-specific B cell memory. To be effective, memory B cells must target the right specificity, with sufficiently high affinity and express the appropriate antibody class t provide the host with long-term immune protection. These three cardinal attributes of antigen-specific B cell memory emerge progressively under the cognate guidance of follicular helper T (TFH) cells following initial priming and antigen re-challenge in vivo. While we know a great deal about circulating antibodies, still little is understood about the development of high-affinity clas-specific memory B cells that ultimately provides B cell-mediated immune protection in vivo. It is our long-term goal to unravel the cellular programs and molecular mechanisms that regulate the stepwise development of antigen-specific B cell memory in vivo. Research Focus: The production of high-affinity antigen-specific antibodies is one powerful means of targeting antigen clearance and is thought to be a major mechanism of action for all vaccines in use today. Upon exposure to foreign antigens, individual helper T (TH) cells and B cells are recruited into the immune response based on the individual specificity of their expressed antigen receptors. What follows is a sequential cascade of antigen-specific programming, functional differentiation and developmental re-programming that produces class switched, high-affinity memory B cells in ways that will be examined mechanistically in the current research proposal. Specific Aims: We will use a murine protein vaccination model to evaluate the changes in transcriptional programming that accompany stepwise antigen-specific memory B cell development. We propose that antigen recognition by specific B cells at different stages of development initiates separable transcriptional programs that mediate productive contact with antigen-specific TFH cells and propagate effective B cell memory. Here, we wil test multiple facets of this central hypothesis with particular focus on the regulation of affinity maturation in early germinal centers (SA-1), ongoing clonal evolution upon antigen recall (SA-2) and the programming and maintenance of antibody class (SA-3) as three defining attributes of antigen-specific B cell memory. Our studies seek to reveal B cell intrinsic mechanisms of memory B cel development that could define unique targets and new strategies to enhance the action and efficacy of future vaccines and targeted immunotherapies.