Chemokine response in B cell development and function

描述(由申请人提供)：趋化因子及其受体已成为造血细胞发育、稳态和功能的重要介体。然而，关于这些分子如何影响B细胞发育和免疫反应的了解相对较少。这项应用的长期目标是从分子上确定趋化因子及其受体如何参与B细胞的选择，以及它们作为成熟淋巴细胞对外来抗原的反应。这一目标的部分原因是我们对一种小鼠品系的初步分析，该品系被设计为缺乏一种信号分子，该分子调节B系细胞内的七螺旋受体信号。使用这些突变体与野生型的、新颖的和已建立的B细胞发育和功能的小鼠模型相结合，我们检验了我们的中心假设，即趋化因子受体信号在体内受到调节，以选择新生成的B细胞，并在免疫反应期间协调适当的B细胞运动。我们从三个具体的目标来阐述这一假说，第一个目标是考察趋化因子受体的反应性是否在B细胞发育过程中作为辅助选择未成熟B细胞的机制而被调节。具体目标2将研究不同的趋化因子如何引导成熟的B细胞在免疫反应的早期阶段激活抗原。上述两个目标的成功实现将阐明调控趋化因子反应如何影响B细胞生物学，尽管将提供有限的对趋化因子受体信号如何在细胞内调控的分子细节的洞察。最终，趋化因子的反应涉及受体信号和随后的肌动蛋白细胞骨架的重组，因为细胞通过化学吸引剂梯度迁移。具体目的3研究B细胞内趋化因子受体信号调控的分子本质及其与肌动蛋白细胞骨架偶联的基础。通过实现这一建议的目标，这些研究不仅将加深我们对趋化因子如何协调免疫系统功能的理解，还将增强我们对导致B细胞耐受和有效体液反应的机制的基础知识。

DESCRIPTION (provided by the applicant): Chemokines and their receptors have emerged as important mediators of hematopoietic cell development, homeostasis, and function. However, relatively little is understood about how these molecules influence B cell development and immune response. The long-term goal of this application is to molecularly define how chemokines and their receptors participate in the selection of B cells and their response to foreign antigens as mature lymphocytes. This objective has been partially motivated by our preliminary analyses of a mouse line engineered to be deficient for a signaling molecule that regulates heptahelical receptor signaling within B lineage cells. Using these mutants in combination with wild-type, novel, and established mouse models of B cell development and function we test our central hypothesis that chemokine receptor signaling is regulated in vivo for selecting newly-generated B cells and orchestrating appropriate B cell movements during an immune response. We address this hypothesis in three specific aims the first of which examines whether chemokine receptor responsiveness is regulated during B cell development as a mechanism that aids in the selection of immature B cells. Specific Aim 2 will investigate how distinct chemokines guide mature B cells upon antigen activation during the early phase of an immune response. Successful execution of the above two Aims will illustrate how regulating chemokine responses may influence B cell biology although will provide limited insight into the molecular details of how chemokine receptor signaling is regulated within the cell. Ultimately, chemokine responses involve receptor signaling and subsequent reorganization of the actin cytoskeleton as cells migrate through a chemoattractant gradient. Specific Aim 3 investigates the molecular nature of how chemokine receptor signaling is regulated within B cells and the basis of its coupling to the actin cytoskeleton. By accomplishing the goals of this proposal, these studies will not only further our understanding of how chemokines orchestrate immune system function, but will also enhance our basic knowledge on the mechanisms leading to B cell tolerance and effective humoral responses.