A New Genetic Tool for Lineage Tracing of Mitotic Cells in Mice

描述(申请人提供)：一种新的遗传工具，用于追踪小鼠有丝分裂细胞的谱系。有丝分裂是体细胞和祖细胞最重要的特征之一。这些细胞的增殖活性对于支持组织功能、替代受损或老化的组织以及维持组织内环境稳定是必不可少的。由于谱系追踪工具的限制，我们仍然对躯体干细胞或前体细胞如何以及在多大程度上对躯体组织的功能和动态平衡做出贡献知之甚少。获得性免疫系统为研究祖细胞增殖爆发和组织动态平衡之间的动态关系提供了最好的例子之一。在对病原体的免疫反应中，抗原特异性淋巴细胞经历了猛烈的克隆性扩张。这些新产生的效应细胞在病原体清除后通过凋亡迅速被移除。一小部分经历过抗原的细胞会发育成记忆细胞，记忆细胞寿命很长，在随后接触相同的抗原时能够进一步扩张。记忆淋巴细胞的产生和动态平衡的维持是持久免疫的关键。到目前为止，记忆淋巴细胞的起源和命运仍不完全清楚。我们正在开发一种独特的Cre/lox介导的小鼠有丝分裂重组系统。使用这种报告系统，成年小鼠的任何增殖细胞都可以用可见的标记进行脉冲标记，以便长期追踪这些细胞及其后代。我们计划使用这种遗传标记系统来标记和追踪来自对病原体的免疫反应的记忆T细胞。我们将研究原发和继发病原体暴露后记忆T细胞的发育、定位和维持。由于实验系统的设计是为了标记任何分裂细胞的后代，该系统也应该有助于追踪和分析淋巴系统以外组织类型中祖细胞或干细胞的克隆行为。我们期待这种标记系统在组织再生、衰老和免疫记忆等领域有广泛的应用。

DESCRIPTION (provided by applicant): A New Genetic Tool for Lineage Tracing of Mitotic Cells in Mice Abstract Mitosis represents one of the most important signatures of somatic stem cells and progenitor cells. The proliferative activity of these cells is essential for supporting tissue functions, replacing damaged or aged tissues, and maintaining tissue homeostasis. Due to the limitations of lineage tracing tools, we still know little about how and to what extent somatic stem or progenitor cells contribute to the function and homeostasis of somatic tissues. The adaptive immune system provides one of the best examples to study the dynamic relationship between the proliferative burst of progenitors and tissue homeostasis. During an immune response to pathogens antigen-specific lymphocytes undergo vigorous clonal expansion. These newly generated effector cells are quickly removed through apoptosis following pathogen clearance. A small fraction of antigen-experienced cells develops into memory cells, which are long lived and are capable of further expansion during subsequent exposure to the same antigen. The generation and homeostatic maintenance of memory lymphocytes are critical for long lasting immunity. Thus far, the origin and fate of memory lymphocytes are still not completely understood. We are developing a unique Cre/lox mediated mitotic recombination system in mice. Using this reporter system, any proliferating cells in adult mice may be pulse labeled with a visible marker for long term tracing of these cells and their descendants. We plan to use this genetic marking system to label and trace memory T cells derived from an immune response to pathogens. We will examine the development, location, and maintenance of memory T cells after primary and secondary pathogen exposure. Because the experimental system is designed to mark the descendants of any dividing cells, the system should also be useful for tracing and analyzing clonal behavior of progenitors or stem cells in tissue types beyond the lymphoid system. We anticipate a broad application of this marking system in the fields such as tissue regeneration, aging, and immunological memory.