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方面发挥关键作用。针对单核细胞增多性李斯特氏菌、巨细胞病毒和弓形虫等病原体的适应性免疫的一个特点是经历过抗原的CD8T细胞之间细胞命运的异质性。大量的初步证据表明，在体内，响应病原体的CD8T细胞的第一次分裂的特征是在信号、细胞命运指定和不对称细胞分裂中具有既定作用的蛋白质的不平等分配。此外，免疫反应的第一个子代T细胞似乎是作为效应器和记忆谱系的前体而不同地注定的。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素是否负责建立不对称分裂所需的细胞骨架特征，以及不对称继承的信号蛋白如何调节子代T细胞的命运差异。这些研究应该为针对生物防御剂的免疫反应和疫苗的合理设计提供一个框架，并解决与淋巴细胞克隆选择原则有关的根本不确定性，以应对传染病。 与公共健康相关：被称为淋巴细胞的特殊白细胞数量增加，以帮助保护我们免受感染。这个项目将提供对如何在一生中保持对再次感染的免疫力的基本见解。这项提议是对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.