Regulation/function of Gamma DELTA T cell differentiatio

Gamma DELTA T 细胞分化的调节/功能

• 批准号: 6719680
• 负责人: ZHINAN YIN
• 金额: $ 12.61万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-26 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6719680
• 关键词: T cell receptor; T lymphocyte; cell differentiation; enzyme linked immunosorbent assay; helper T lymphocyte; interferon gamma; interleukin 4; laboratory mouse; leukocyte activation /transformation; northern blottings; polymerase chain reaction

gamma-delta T cells have unique features in comparison to alpha-beta T cells. It has now become clear that gamma-delta T cells recognize non-peptide and non-processed bacterial and environmental antigens, as well as stress-associated antigens expressed on epithelial cells and on certain tumor lines and primary carcinomas. However, understanding of gamma-delta T cell biology, especially cytokine responses, has lagged far behind that of alpha-beta T cells. Preliminary studies from our lab have shown that while polarization of native gamma-delta T cells in vitro can yield cells that produce IFN-gamma or IL-4 (like alpha-beta T cells), gamma-delta T cells default to a Th1 pathway, predominantly producing IFN-gamma, even in the presence of IL-4. Moreover, IL-12 signaling in gamma-delta T cells is constitutive and dissociated from IL-4-mediated regulation. Based on these data, the hypothesis is raised that the molecular mechanisms for gamma-delta T cell differentiation, especially the factors that modulate gamma-delta T cell polarization, are different from those in alpha-beta CD4+ T cells, and that gamma-delta T cells play important roles in early intracellular pathogen protection and in tumor immunity through their predominant production of IFN-gamma. To address these hypotheses, the following specific aims will be carried out: Aim l. To define the factors that regulate gamma-delta T cell IFN-gamma production in vitro. Aim 2. To define the factors that modulate gamma-delta T cell IL-4 production in vitro. Aim 3. To define in vivo the roles of gamma-delta T cells in regulating CD4+ T cell polarization. Aim 4. To define the role of IFN-gamma produced by gamma-delta T cells in pathogen protection and in tumor immunity. Study of the mechanisms of gamma-delta T cell differentiation in vitro and their functions in vivo is critical for understanding the function of gamma-delta T cells in immune responses.

与α-βT细胞相比，伽马-βT细胞具有独特的功能。现在已经很清楚，伽马-德尔塔T细胞识别非肽和未加工的细菌和环境抗原，以及在上皮细胞、某些肿瘤株和原发癌上表达的应激相关抗原。然而，对伽马-德尔塔T细胞生物学，特别是细胞因子反应的了解，远远落后于阿尔法-贝塔T细胞。我们实验室的初步研究表明，虽然自然伽马-三角洲T细胞在体外极化可以产生产生干扰素-伽马或IL-4的细胞(如阿尔法-βT细胞)，但伽马-三角洲T细胞默认为Th1途径，即使在存在IL-4的情况下也主要产生干扰素-伽马。此外，γ-增量T细胞中的IL-12信号是结构性的，与IL-4介导的调节无关。基于这些数据，提出了一个假设，即γ-Delta T细胞分化的分子机制，特别是调节γ-Delta T细胞极化的因素，与α-βCD4+T细胞不同，并且Gamma-Delta T细胞在早期细胞内病原体保护和肿瘤免疫中发挥着重要作用，其主要产生干扰素-γ。为了解决这些假说，将开展以下具体目标：目的：L。明确体外调节γ-βT细胞干扰素-γ产生的因素。目的2.确定在体外调节γ-Delta T细胞产生IL-4的因素。目的3.在体内明确γ-Delta T细胞在调节CD4+T细胞极化中的作用。目的4.明确γ-Delta T细胞产生的干扰素-γ在病原体保护和肿瘤免疫中的作用。研究γ-Delta T细胞在体外分化的机制及其在体内的功能，对于了解γ-Delta T细胞在免疫应答中的作用至关重要。