Asymmetric Lymphocyte Division in the Immune Response

免疫反应中淋巴细胞的不对称分裂

• 批准号: 9108825
• 负责人: STEVEN L REINER
• 金额: $ 40万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9108825
• 关键词: 3-Dimensional; 4D Imaging; Activated Lymphocyte; Activities of Daily Living; Address; Adopted; Antibodies; Autoimmunity; B-Lymphocytes; Behavior; Biological; Cell Polarity; Cell division; Cells; Characteristics; Chimeric Proteins; Clonal Expansion; Communicable Diseases; Data; Daughter; Development; Engineering; Equilibrium; Exhibits; Health; Heterogeneity; Host Defense; Image; Immune; Immune response; Immunity; Immunization; Immunoglobulin Class Switching; Immunoglobulin M; Immunoglobulins; Inequality; Infection; Inherited; Leukocytes; Life; Lymphocyte; Maintenance; Mediating; Memory; Memory B-Lymphocyte; Methodology; Mus; Mutant Strains Mice; Plasma Cells; Plasmablast; Play; Property; Proteins; Reaction; Reagent; Reporter; Resolution; Retrieval; Role; Siblings; Sister; Stem cells; Structure of germinal center of lymph node; Structure of thyroid parafollicular cell; T-bet protein; Testing; Uncertainty; Vaccinated; Vaccines; Work; atypical protein kinase C; cell mediated immune response; cellular imaging; daughter cell; in vitro Model; in vivo; meetings; microbial; novel; plasma cell differentiation; regenerative; research study; response; self-renewal

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.

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发挥着关键作用。活化淋巴细胞的细胞命运多样化对于 达到长期免疫力所需的再生状态。然而，人们对 B 细胞命运多样性产生的机制知之甚少。大量初步数据表明，B 细胞可以利用进化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。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主要特征。该提案开发了新的方法来对免疫反应过程中分裂的 B 细胞的特征进行成像。该项目的目的是测试 B 细胞 Bcl-6、Pax5 和 T-bet 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能调节关键的细胞命运决定。这些实验将测试以下假设：迭代地使用不对称分裂来满足终末分化和自我更新的相反需求，并通过调节生发中心进入和类别转换选择来完善和多样化抗体的功能特性。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 B 细胞分裂，以及不对称遗传蛋白如何介导子代 B 细胞的命运差异。这些研究应该为针对微生物制剂的免疫反应和疫苗的合理工程提供一个框架。该项目还应该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。