The Development and Function of CD8+ innate-like lymphocytes

CD8先天样淋巴细胞的发育和功能

• 批准号: 8868911
• 负责人: Shannon A. Carty
• 金额: $ 13.38万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8868911
• 关键词: Adoptive Transfer; Bacterial Infections; Biochemical; Biological; Biological Assay; Bone Marrow; Boxing; CD44 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cell surface; Cells; Characteristics; Chimera organism; Chronic; Data; Development; Development Plans; Effector Cell; Embryonic Development; Environment; Fostering; Frequencies; Future; Generations; Grant; Hematology; IL2RB gene; Immune; Immune response; Immune system; Immunotherapeutic agent; Immunotherapy; In Vitro; Infection; Interferons; Interleukin-4; LCP2 gene; Laboratories; Lead; Leukocytes; Ligands; Listeria monocytogenes; Lymphocyte; Lymphocyte Subset; Mediating; Mediator of activation protein; Medical; Memory; Mentorship; Methods; Modeling; Molecular; Mus; Nature; Pathway interactions; Pennsylvania; Peptides; Phenylalanine; Phosphoproteins; Physicians; Point Mutation; Population; Production; Proteins; Receptor Signaling; Research; Research Personnel; Role; Scientist; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Surface; T Cell Receptor Signaling Pathway; T memory cell; T-Cell Antigen Receptor Specificity; T-Cell Development; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Thymus Gland; Training; Transgenic Organisms; Tyrosine; Universities; Vaccines; Viral; Virus Diseases; Wild Type Mouse; base; career; career development; congenic; cytokine; design; genetic approach; human ZNF145 protein; immune function; improved; in vivo; insight; novel; oncology; pathogen; research and development; response; skills; src Homology Region 2 Domain; thymocyte; transcription factor; tumor

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.

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 (ILL)。 CD8+ ILL 的特征在于激活/记忆标记 CD44 和 CD122 的表达、T 盒转录因子 Eomesodermin (Eomes) 的表达以及产生的能力体外刺激后，这些 CD8+ ILL 会通过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）的胸腺细胞产生 IL-4 介导的细胞外机制而迅速形成。描述了一个五年职业发展计划和研究策略，以在 Gary Koretzky 博士的指导下，利用美国优秀的培训环境，发展成为一名实验室医师学术科学家的独立职业。在宾夕法尼亚大学血液学/肿瘤学系，该计划将帮助候选人培养成为独立研究者所需的技能，评估 ILL 在免疫反应中的作用。拟议的研究策略旨在研究 ILL 的新机制。目标 1 的重点是阐明 Eomes 和 IL-4 信号通路如何调节 CD8+ ILL 发育。目前关于 CD8+ ILL 功能的数据很少，因此，目标 2 旨在研究 CD8+ ILL 在响应细菌和病毒病原体中的作用。