Asymmetric Lymphocyte Division in the Immune Response

描述（由申请方提供）：B淋巴细胞及其产生的抗体在宿主防御中起关键作用。活化的淋巴细胞的细胞命运多样化是至关重要的， 达到长寿免疫所需的再生状态。然而，对产生B细胞命运多样性的机制知之甚少。大量的初步数据表明，B细胞可以使用进化上保守的策略来分配不等量的关键成分，从而使其子细胞的命运和功能多样化。这个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主要特征。该提案开发了新的方法来成像免疫反应过程中分裂的B细胞的特征。该项目的目的是测试B细胞Bcl-6、Pax 5和T-bet的三种不同转录调节因子的不平等细胞遗传的重要性，已知每种转录调节因子都调节关键的细胞命运决定。实验将测试不对称分裂迭代地用于满足末端分化和自我更新的相反需求，以及通过调节生发中心进入和类别转换选择来细化和多样化抗体的功能特性的假设。该项目还将研究细胞极性的祖先调节因子是否负责建立不对称的B细胞分裂，以及不对称遗传的蛋白质如何介导子代B细胞的命运差异。这些研究应提供一个框架，合理的工程免疫反应和疫苗对微生物剂。该项目还应解决有关淋巴细胞克隆选择原理的基本不确定性，以应对传染病或在我们的免疫细胞攻击我们自己的情况下。

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.