Regulation/function of Gamma DELTA T cell differentiatio

Gamma DELTA T 细胞分化的调节/功能

• 批准号: 6511743
• 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/6511743
• 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-β T细胞相比，γ-δ T细胞具有独特的特征。现在已经清楚的是，γ-δ T细胞识别非肽和未加工的细菌和环境抗原，以及在上皮细胞和某些肿瘤细胞系和原发性癌上表达的应激相关抗原。 然而，对γ-δ T细胞生物学，特别是细胞因子反应的理解远远落后于α-β T细胞。我们实验室的初步研究表明，虽然体外天然γ-δ T细胞的极化可以产生产生IFN-γ或IL-4的细胞（如α-β T细胞），但γ-δ T细胞默认为Th 1途径，主要产生IFN-γ，即使在IL-4存在的情况下。 此外，γ-δ T细胞中的IL-12信号传导是组成性的，并且与IL-4介导的调节分离。 基于这些数据，提出了以下假设：γ-δ T细胞分化的分子机制，特别是调节γ-δ T细胞极化的因子，与α-β CD 4 + T细胞中的那些不同，并且γ-δ T细胞通过其主要产生IFN-γ在早期细胞内病原体保护和肿瘤免疫中起重要作用。 为了解决这些假设，将实现以下具体目标：确定体外调节γ-δ T细胞IFN-γ产生的因素。目标二。 确定体外调节γ-δ T细胞IL-4产生的因素。目标3。 明确γ-δ T细胞在体内调节CD 4 + T细胞极化中的作用。目标4。 明确γ-δ T细胞产生的IFN-γ在病原体保护和肿瘤免疫中的作用。 研究γ-δ T细胞的体外分化机制及其在体内的功能对于理解γ-δ T细胞在免疫应答中的功能至关重要。