Regulation and Function of Polarity and Asymmetric Cell Division in Immunity

 描述(申请人提供)：在对微生物病原体的免疫反应中，识别微生物的幼稚T淋巴细胞必须产生两种不同类型的后代。效应细胞用于提供急性宿主防御，而记忆细胞提供在宿主再次遇到病原体时快速回忆反应的能力。先前的研究已经证明，单个单纯的CD8+T淋巴细胞能够产生免疫反应所需的所有不同的细胞命运。然而，单个激活的T淋巴细胞产生效应和记忆注定的后代的过程，以及这些分化途径开始分化的时间，仍然没有答案。我们最近发现，T淋巴细胞可以进行不对称分裂，产生两个不同的子细胞，这两个子细胞的命运不同于效应器和记忆谱系。活性亲本R01赠款的总体目标是研究不对称CD8+T细胞分裂的功能后果，并阐明不对称分裂导致效应T细胞和记忆T细胞命运指定的机制。在这一修订应用中，我们建议开发新的单细胞方法来定义单个CD8+T淋巴细胞在体内分化时对微生物病原体的转录和表观遗传学路线图。本文提出的目标的实现可能会对不对称分裂影响细胞命运指定和功能的基本机制产生重要的见解，并可能有助于为疫苗的合理开发提供一个框架。

 DESCRIPTION (provided by applicant): During an immune response against a microbial pathogen, naïve T lymphocytes that recognize the microbe must give rise to two distinct types of progeny. Effector cells serve to provide acute host defense, whereas memory cells provide the ability to mount rapid recall responses should the host re-encounter the pathogen. Prior studies have demonstrated that a single naïve CD8+ T lymphocyte is capable of generating all of the diverse cellular fates necessary for an immune response. The process by which a single activated T lymphocyte yields effector- and memory-fated progeny, and the timing at which these differentiation pathways begin to diverge, however, remains unanswered. We have recently shown that a T lymphocyte can undergo asymmetric division to give rise to two daughter cells that are differentially fated toward the effector and memory lineages. The overall goals of the active parent R01 grant are to investigate the functional consequences of asymmetric CD8+ T cell division and to elucidate the mechanisms by which asymmetric division leads to specification of the effector and memory T cell fates. In this revision application, we propose to develop novel single cell approaches to define the transcriptomic and epigenetic roadmap of an individual CD8+ T lymphocyte as it differentiates in vivo in response to a microbial pathogen. Accomplishment of the aims proposed herein is likely to yield important insights into the fundamental mechanisms by which asymmetric division influences cell fate specification and function, and may help to provide a framework for the rational development of vaccines.