Asymmetric T cell division initiating adaptive immunity and colitis

不对称 T 细胞分裂启动适应性免疫和结肠炎

• 批准号: 7806296
• 负责人: John T Chang
• 金额: $ 0.11万
• 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: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7806296
• 关键词: Address; Animal Model; Antigen-Presenting Cells; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Separation; Cell division; Cells; Colitis; Data; Daughter; Decision Making; Effector Cell; Ensure; Environment; Flow Cytometry; Goals; Heterogeneity; Image; Immune response; Immunity; Immunofluorescence Microscopy; Immunologic Receptors; In Vitro; Individual; Infection; Inflammatory Bowel Diseases; Intestinal Mucosa; Intestines; Laboratories; Leishmania major; Lymphocyte; Mediating; Memory; Methodology; Microbe; Mitotic spindle; Molecular; Morphology; Pathogenesis; Play; Population; Proteins; Receptor Signaling; Regulation; Research Personnel; Role; Side; Signaling Molecule; Site; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Work; base; cell fate specification; commensal microbes; daughter cell; in vivo; insight; microbial; new therapeutic target; pathogen; prevent; programs; response; Address; Animal Model; Antigen-Presenting Cells; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Separation; Cell division; Cells; Colitis; Data; Daughter; Decision Making; Effector Cell; Ensure; Environment; Flow Cytometry; Goals; Heterogeneity; Image; Immune response; Immunity; Immunofluorescence Microscopy; Immunologic Receptors; In Vitro; Individual; Infection; Inflammatory Bowel Diseases; Intestinal Mucosa; Intestines; Laboratories; Leishmania major; Lymphocyte; Mediating; Memory; Methodology; Microbe; Mitotic spindle; Molecular; Morphology; Pathogenesis; Play; Population; Proteins; Receptor Signaling; Regulation; Research Personnel; Role; Side; Signaling Molecule; Site; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Work; base; cell fate specification; commensal microbes; daughter cell; in vivo; insight; microbial; new therapeutic target; pathogen; prevent; programs; response

DESCRIPTION (provided by applicant): A hallmark of adaptive immunity is heterogeneity of T cell fates in response to microbial pathogens. This [sic] goal of this project is to understand the molecular basis by which these cell fate decisions are made. Preliminary data has [sic] suggested that asymmetric cell division might be a mechanism utilized by T cells to generate cell fate heterogeneity during immune responses to microbial pathogens. Asymmetric cell division is an evolutionary conserved mechanism used to confer disparate fates among daughter cells. This mechanism involves the polarized alignment of determinants of cell fate perpendicular to the mitotic spindle, thus ensuring the unequal inheritance of critical molecules and divergence of daughter cell fate. Activation of a naive T cell by its antigen-presenting cell (APC) during an immune response is characterized by polarization of immune receptors and signaling molecules to the site of contact. Recent in vivo imaging studies suggest that an activated T cell engages in sustained contact with ARC until its first cellular division. This proposal tests the hypothesis that this prolonged contact of the T cell with ARC coordinates the asymmetric partitioning of proteins that mediate signaling, cell fate specification, and asymmetric cell division. In this way, asymmetric T cell division during an immune response could give rise to daughter cells with distinct fates and ensure that appropriate diversity of cell fate arises from the descendants of a single lymphocyte. This proposal aims to answer three questions. First, is asymmetric cell division a universal feature of the initial divisions of the CD4+ T cell response to microbial pathogens? This will be addressed by using immunofluorescence microscopy to determine whether asymmetric cell division is evident in CD4+ T cells responding to various microbial pathogens in vivo. Second, what are the fates of the initial daughter and granddaughter CD4+ T cells? This will be addressed by characterizing daughter cells, sorted by flow cytometry, arising from initial asymmetric T cell divisions of the immune response. Third, is there a role for asymmetric cell division in the differentiation of colitogenic CD4+ T cells? This will be addressed by characterizing the morphology and fates of activated CD4+ T cells in an animal model of colitis. Intestinal microbes trigger an aberrant CD4+ T cell immune response that ultimately leads to inflammatory bowel disease (IBD). The goal of this proposal is to understand how cell fate decisions are made during an immune response and how distinct T cell subsets that cause or prevent IBD are generated. Understanding the mechanism by which this occurs is likely to provide important insights into the pathogenesis of IBD and may identify new targets for therapy.

描述（由申请人提供）： 适应性免疫的标志是响应微生物病原体的T细胞命运的异质性。该项目的这个[SIC]目标是了解这些细胞命运决定的分子基础。初步数据[SIC]表明，在对微生物病原体的免疫反应期间，不对称细胞分裂可能是T细胞使用的一种机制来产生细胞命运异质性。 不对称细胞分裂是一种进化保守的机制，用于在子细胞中赋予不同的命运。该机制涉及垂直于有丝分裂纺锤体的细胞命运决定因素的两极分化比对，从而确保了临界分子的不相等遗传和子细胞命运的差异。免疫反应过程中通过其抗原呈递细胞（APC）激活幼稚的T细胞的特征是免疫受体的极化和信号分子与接触部位的偏振。最近的体内成像研究表明，活化的T细胞与ARC持续接触，直到其首次细胞分裂为止。该提案检验了以下假设：T细胞与ARC的这种延长接触是介导信号传导，细胞命运规范和不对称细胞分裂的蛋白质的不对称分配。这样，免疫反应期间的不对称T细胞分裂可能会导致具有不同命运的子细胞，并确保单个淋巴细胞的后代产生适当的细胞命运多样性。 该建议旨在回答三个问题。首先，不对称细胞分裂是CD4+ T细胞反应对微生物病原体的初始分裂的通用特征吗？这将通过使用免疫荧光显微镜来确定在体内响应各种微生物病原体的CD4+ T细胞中是否明显不对称细胞分裂来解决这一点。其次，最初的女儿和孙女CD4+ T细胞的命运是什么？这将通过表征由流式细胞仪排序的子细胞来解决这，这是由免疫反应的初始不对称T细胞分裂引起的。第三，不对称细胞分裂在分化的性别CD4+ T细胞中是否有作用？这将通过表征结肠炎动物模型中活化的CD4+ T细胞的形态和命运来解决这一点。 肠道微生物会引发异常的CD4+ T细胞免疫反应，最终导致炎症性肠病（IBD）。该提案的目的是了解在免疫反应期间如何做出细胞命运决策，以及如何产生或预防IBD的不同T细胞子集。了解这种情况的机制可能会为IBD的发病机理提供重要的见解，并可能确定治疗的新目标。