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。抗单核细胞增生李斯特菌、LCMV病毒和刚地弓形虫等病原体的适应性免疫的一个标志是抗原经历的CD8+ T细胞命运的异质性。本提案中概述的大量初步证据表明，CD8+ T细胞在体内响应病原体的第一次分裂的特征是蛋白质的不平等分配，这些蛋白质在信号传导、细胞命运规范和不对称细胞分裂中起着既定的作用。此外，免疫反应的第一个子T细胞作为效应细胞和记忆细胞谱系的前体似乎有不同的命运。该项目将测试不对称细胞分裂是否是CD8+ T细胞对抗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，以及不对称遗传信号蛋白如何介导子代T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生物防御剂的疫苗提供一个框架，并解决有关淋巴细胞克隆选择原理在应对传染病方面的根本不确定性。

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.