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: 8354211
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8354211
• 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; Genetic; 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; 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. 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.

描述（由适用提供）：胸腺中发生的常规和非规定T细胞。具有通常与先天免疫细胞相关的特征的非惯性T细胞称为先天样淋巴细胞（ILLS）。我们和其他人描述了CD8+疾病的种群，其特征是激活/记忆标记CD44和CD122，T-box转录因子Eomesodermin（Eomes）的表达以及在体外刺激后快速产生IFN的能力。这些CD8+疾病是通过由IL-4产生的细胞肢体机制发展出来的，这些机制是由胸腺细胞群体群的人群介导的，这些胸腺细胞表达了临床前细胞性白血病锌指蛋白（PLZF），这是一种已知的先天细胞转录调节剂。该建议描述了一项为期5年的职业发展计划和研究策略，以发展为基于实验室的学术物理科学家的独立职业。在加里·科雷茨基（Gary Koretzky）博士的心态下，并在宾夕法尼亚大学的血液学/肿瘤学系中使用了杰出的培训环境，该计划将有助于候选人培养她成为一名独立研究人员所需的技能，以评估疾病在免疫反应中的作用。拟议的研究策略旨在研究细胞因子驱动T细胞发育的新机制，并定义CD8+疾病的功能。 AIM 1的重点是采用体外和体内策略，是阐明EOMES和IL-4信号通路如何调节CD8+疾病的发育。目前，有关CD8+疾病功能的数据很少。因此，AIM 2旨在研究CD8+疾病对细菌和病毒病原体的作用。 公共卫生相关性：当免疫系统无法充分保护宿主免受感染和肿瘤的影响时，医疗疗法（即疫苗或免疫疗法）可能有助于改善免疫功能。该提案描述了一种表征新描述的免疫细胞种群的发育和功能的策略，称为CD8+先天样淋巴细胞（CD8+ ILLS）。了解CD8+疾病在免疫反应中的作用可能导致未来治疗应用的潜力。