Asymmetric CD8+ T Cell Division in the Initiation of Immunity

描述（由申请人提供）：CD8+ T细胞在宿主防御与生物防御相关的微生物中发挥关键作用。针对诸如单核细胞增多性李斯特菌、LCMV病毒和刚地弓形虫的因子的适应性免疫的标志是抗原经历的CD8+ T细胞之间的细胞命运的异质性。本提案中概述的大量初步证据表明，体内应答病原体的CD8+ T细胞的第一次分裂的特征在于在信号传导、细胞命运规范和不对称细胞分裂中具有既定作用的蛋白质的不均等分配。此外，免疫应答的第一个子T细胞似乎作为效应和记忆谱系的前体而具有不同的命运。该项目将测试不对称细胞分裂是否是CD8+ T细胞对病原体反应的一般特征，细胞极性的祖先调节因子是否负责建立不对称分裂所需的细胞骨架特征，以及不对称遗传的信号蛋白如何介导子代T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生物防御剂，并解决基本的不确定性淋巴细胞的克隆选择的原则，以应对传染病。 公共卫生相关性：特殊的白色血细胞，称为淋巴细胞，数量增加，以帮助保护我们免受感染。这个项目将提供基本的洞察力如何对再感染的免疫力是维持一个人的整个生命。这项建议是对NIAID赞助的生物防御研究的持续倡议的回应。

DESCRIPTION (provided by applicant): CD8+ T cells play a critical role in host defense against microbes pertinent to biodefense. A hallmark of adaptive immunity against agents such as Listeria monocytogenes, LCMV virus, and Toxoplasma gondii is heterogeneity of cell fate among antigen-experienced CD8+ T cells. Substantial preliminary evidence outlined in this proposal indicates that the first division of a CD8+ T cell responding to a pathogen, in vivo, is characterized by unequal partitioning of proteins with established roles in signaling, cell fate specification, and asymmetric cell division. In addition, the first daughter T cells of the immune response appear to be differentially fated as precursors of the effector and memory lineages. This project will test whether asymmetric cell division is a general feature of the CD8+ T cell response against pathogens, whether ancestral regulators of cell polarity are responsible for establishing cytoskeletal features necessary for asymmetric division, and how asymmetrically inherited signaling proteins could mediate fate disparity in daughter T cells. These studies should provide a framework for rational engineering of immune responses and vaccines against agents of biodefense, and address fundamental uncertainties regarding the principle of clonal selection of lymphocytes in response to infectious diseases. PUBLIC HEALTH RELEVANCE: Specialized white blood cells, called lymphocytes, increase in number to help protect us against infections. This project will provide fundamental insight into how immunity against re-infection is maintained for one's entire life. This proposal is a response to a continuing initiative in Biodefense research sponsored by the NIAID.