Asymmetric CD8+ T Cell Division in the Initiation of Immunity

免疫启动过程中 CD8 T 细胞的不对称分裂

• 批准号: 7473390
• 负责人: STEVEN L REINER
• 金额: $ 38.69万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 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 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7473390
• 关键词: Actins; Acute; Address; Antigen-Presenting Cells; Antigens; Blood; CD8B1 gene; Cell Polarity; Cell division; Cells; Communicable Diseases; Communication; Cytoskeletal Modeling; Cytoskeleton; Daughter; Developmental Biology; Discipline; Distal; Effector Cell; Engineering; Equilibrium; Exhibits; Genetic; Heterogeneity; Host Defense; Image; Immune; Immune Cell Activation; Immune response; Immunity; In Situ; Infection; Inherited; Interferon Type II; Leukocytes; Life; Listeria; Listeria monocytogenes; Listeriosis; Lymphocyte; Lymphocyte Activation; Lymphocytic choriomeningitis virus; Mediating; Memory; Microbe; Mitotic spindle; Morphology; National Institute of Allergy and Infectious Disease; Natural regeneration; Normal Cell; Numbers; Parents; Play; Proteins; Public Health; Recording of previous events; Regulation; Research; Role; Signal Pathway; Signal Transduction; Signaling Protein; T-Cell Activation; T-Lymphocyte; Testing; Time; Toxoplasma gondii; Uncertainty; Vaccines; Virus; biodefense; experience; in vivo; insight; pathogen; research study; response; segregation; self-renewal

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.

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着关键作用。针对单核细胞增多性李斯特菌、LCMV 病毒和弓形虫等病原体的适应性免疫的一个标志是经历过抗原的 CD8+ T 细胞之间细胞命运的异质性。该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点是在信号传导、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匀分配。此外，免疫反应的第一个子代 T 细胞作为效应细胞和记忆谱系的前体似乎有着不同的命运。该项目将测试不对称细胞分裂是否是 CD8+ T 细胞针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，以及不对称遗传信号蛋白如何介导子代的命运差异T 细胞。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工程提供一个框架，并解决有关淋巴细胞克隆选择原理以应对传染病的基本不确定性。 公共卫生相关性：特殊的白细胞（称为淋巴细胞）数量增加有助于保护我们免受感染。该项目将提供关于如何在人的一生中维持针对再次感染的免疫力的基本见解。该提案是对 NIAID 赞助的生物防御研究持续倡议的回应。