Asymmetric Lymphocyte Division in the Immune Response

描述(由申请人提供)：B淋巴细胞及其产生的抗体在宿主防御中起着关键作用。活化淋巴细胞的细胞命运多样化对于 达到长寿免疫所需的再生状态。然而，产生B细胞命运多样性的机制却鲜为人知。大量的初步数据表明，B细胞可以通过一种进化保守的策略来分配不同数量的关键成分，从而使其子代细胞的命运和功能多样化。该项目将测试不对称细胞分裂是否是B细胞介导的免疫反应的基本特征。该提案开发了新的方法来成像免疫反应过程中B细胞分裂的特征。该项目的目的是测试三种不同的B细胞转录调控因子Bcl-6、Pax5和T-bet的细胞遗传不平等的重要性，已知每一种转录调控因子都调节关键的细胞命运决定。实验将验证这样的假设，即反复使用不对称分裂来满足末端分化和自我更新的对立需求，以及通过调节生发中心进入和类别切换选择来提炼和多样化抗体的功能特性。该项目还将研究祖先对细胞极性的调节是否对建立不对称的B细胞分裂负责，以及不对称遗传蛋白如何调节子代B细胞的命运差异。这些研究应该为合理设计免疫反应和针对微生物制剂的疫苗提供一个框架。这个项目还应该解决有关淋巴细胞克隆选择原则的根本不确定性，以应对传染病或当我们的免疫细胞攻击我们自己的时候。

DESCRIPTION (provided by applicant): B lymphocytes and the antibodies they produce play a critical role in host defense. Cell fate diversification of activated lymphocytes is essential to achieve the regenerative state required for long-lived immunity. The mechanisms responsible for generating B cell fate diversity, however, are poorly understood. Substantial preliminary data suggest B cells can diversify the fates and functions of their daughter cells using an evolutionarily conserved strategy to allocate unequal amounts of key components. This project will test whether asymmetric cell division is a cardinal feature of the B cell- mediated immune response. The proposal develops novel methodologies to image the characteristics of dividing B cells during the course of an immune response. The aims of the project are to test the importance of unequal cellular inheritance of three different transcriptional regulators of B cells Bcl-6, Pax5, and T-bet, each of which is known to regulate critical cell fate decisions. The experiments will test the hypotheses that asymmetric division is iteratively used to meet the opposing demands of terminal differentiation and self-renewal, as well to refine and diversify the functional properties of antibodies by regulating germinal center entry and class switch choice. This project will also examine whether ancestral regulators of cell polarity are responsible for establishing asymmetric B cell division, and how asymmetrically inherited proteins could mediate fate disparity in daughter B cells. These studies should provide a framework for rational engineering of immune responses and vaccines against microbial agents. This project should also address fundamental uncertainties regarding the principle of clonal selection of lymphocytes in response to infectious diseases or during situations when our immune cells attack our own selves.