The Development and Function of CD8+ innate-like lymphocytes

描述(申请人提供)：胸腺发育常规和非常规T细胞。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CD8+ILS的群体，其特征是表达激活/记忆标记CD44和CD122，表达T-box转录因子Eomesodermin(EOMES)，以及在体外刺激后快速产生干扰素。这些CD8+疾病是通过一种细胞外机制发展起来的，这种机制是由一群表达早幼粒细胞白血病锌指蛋白(PLZF)的胸腺细胞产生IL-4介导的，PLZF是一种已知的天然细胞转录调节因子。本提案描述了一项为期5年的职业发展计划和研究战略，以发展作为实验室学术内科科学家的独立职业生涯。在Gary Koretzky博士的指导下，并利用宾夕法尼亚大学血液学/肿瘤学系出色的培训环境，该计划将帮助候选人培养所需的技能，以成为一名评估疾病在免疫反应中的作用的独立调查员。提出的研究策略旨在研究细胞因子驱动T细胞发育的新机制，并确定CD8+ILS的功能。采用体外和体内互补的策略，目标1的重点是阐明eome和IL-4信号通路如何调控CD8+疾病的发育。目前关于CD8+ILS功能的数据很少。因此，AIM 2旨在研究CD8+ILS在细菌和病毒病原体应答中的作用。 公共卫生相关性：当免疫系统不能充分保护宿主免受感染和肿瘤侵袭时，医学疗法(即疫苗或免疫疗法)可能有助于提高免疫功能。这项建议描述了一种新描述的免疫细胞群体的发育和功能的策略，称为CD8+类先天淋巴细胞(CD8+ILS)。了解CD8+疾病在感染免疫反应中的作用可能有助于未来的治疗应用。

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. PUBLIC HEALTH RELEVANCE: When the immune system fails to adequately protect the host from infections and tumors, medical therapies (i.e., vaccines or immunotherapy) may help to improve immune function. This proposal describes a strategy to characterize the development and function of a newly described population of immune cells, called CD8+ innate-like lymphocytes (CD8+ ILLs). Understanding of the role of CD8+ ILLs in immune responses to infection may lead to the potential for future therapeutic applications.