The Development and Function of CD8+ innate-like lymphocytes

描述（由申请人提供）：常规和非常规T细胞在胸腺中发育。具有先天免疫细胞特征的非常规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个CD8+ ill群体，其特征是激活/记忆标记CD44和CD122的表达，T-box转录因子Eomes的表达以及在体外刺激后快速产生IFN¿的能力。早幼粒细胞白血病锌指蛋白（PLZF）是一种已知的先天细胞转录调节因子，这些CD8+疾病通过IL-4介导的胸腺细胞群体产生的细胞外源性机制发生。该提案描述了一个五年的职业发展计划和研究策略，以发展一个独立的职业生涯，作为一个实验室为基础的学术医师科学家。在Gary Koretzky博士的指导下，并利用宾夕法尼亚大学血液学/肿瘤学部门出色的培训环境，该计划将帮助候选人培养成为一名独立研究者所需的技能，以评估疾病在免疫反应中的作用。我们提出的研究策略旨在探索细胞因子驱动T细胞发育的新机制，并明确CD8+ ill的功能。采用体外和体内互补的策略，Aim 1的重点是阐明Eomes和IL-4信号通路如何调节CD8+ ILL的发展。目前关于CD8+ il功能的数据很少。因此，Aim 2旨在研究CD8+ ill在应对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.