The development and function of CD8+ innate-like lymphocytes

描述（由申请方提供）：常规和非常规T细胞在胸腺中发育。具有通常与先天免疫细胞相关的特征的非常规T细胞被称为先天样淋巴细胞（ILLs）。我们和其他人已经描述了一群CD 8 + ILLs，其特征在于表达活化/记忆标记物CD 44和CD 122，表达T盒转录因子Eomesodermin（Eomes），并能够在体外刺激后快速产生IFN γ。这些CD 8 + ILL通过细胞外源性机制发展，该机制由表达早幼粒细胞白血病锌指蛋白（PLZF）（一种已知的先天细胞转录调节因子）的胸腺细胞群产生的IL-4介导。该提案描述了一个5年的职业发展计划和研究战略，以发展作为一个实验室为基础的学术医生科学家的独立职业生涯。在加里Koretzky博士的指导下，并利用宾夕法尼亚大学血液学/肿瘤学部门的优秀培训环境，该计划将帮助候选人培养成为独立研究者所需的技能，以评估ILLs在免疫反应中的作用。该研究策略旨在探讨细胞因子驱动T细胞发育的新机制，并确定CD 8 + ILLs的功能。采用互补的体外和体内策略，目标1的重点是阐明Eomes和IL-4信号通路如何调节CD 8 + ILL的发展。目前关于CD 8 + ILLs功能的数据很少。因此，目的2旨在研究CD 8 + ILLs在响应细菌和病毒病原体中的作用。

DESCRIPTION (provided by applicant): Conventional and non-conventional T cells develop in the thymus. Non-conventional T cells that have features typically associated with innate immune cells are termed innate-like lymphocytes (ILLs). We and others have described a population of CD8+ ILLs, characterized by expression of the activation/memory markers CD44 and CD122, expression of the T-box transcription factor Eomesodermin (Eomes) and ability to produce IFN� rapidly after ex vivo stimulation. These CD8+ ILLs develop via a cell-extrinsic mechanism mediated by IL-4 production from a population of thymocytes that express promyelocytic leukemia zinc finger protein (PLZF), a known transcriptional regulator of innate cells. This proposal describes a 5-year career development plan and research strategy to develop an independent career as a laboratory-based academic physician scientist. Under the mentorship of Dr. Gary Koretzky, and utilizing the outstanding training environment in the Division of Hematology/Oncology at the University of Pennsylvania, this plan will help the candidate foster the skills needed for her to become an independent investigator evaluating the role of ILLs in the immune responses. The proposed research strategy aims to investigate the novel mechanism of cytokine driven T cell development and to define the function of CD8+ ILLs. Employing complementary in vitro and in vivo strategies, the focus of Aim 1 is to elucidate how Eomes and the IL-4 signaling pathway regulate CD8+ ILL development. There is currently scant data regarding the function of CD8+ ILLs. Therefore, Aim 2 is designed to investigate the role of CD8+ ILLs in response to bacterial and viral pathogens.