Mechanism and function of T cell differentiation

T细胞分化的机制和功能

• 批准号: 6776072
• 负责人: ZHINAN YIN
• 金额: $ 12.26万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-15 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6776072
• 关键词: T cell receptor; T lymphocyte; cell differentiation; cellular immunity; cytokine; cytotoxic T lymphocyte; flow cytometry; genetically modified animals; helper T lymphocyte; immune response; immunoregulation; interferon gamma; interleukin 4; laboratory mouse; leukocyte activation /transformation; mitogen activated protein kinase; neoplasm /cancer immunology; ovalbumin; protein signal sequence; protein structure function; tissue /cell culture

DESCRIPTION (provided by applicant): Gamma-delta T cells have unique features in comparison to alpha-beta T cells. It now has 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 epithelium and on primary carcinomas. Both in vitro and in vivo studies have demonstrated that Gamma-delta T cells can be differentiated into IFN-gamma (Th1-like)- and IL-4 (Th2-like)-producing cells. However, the molecular mechanisms underlying such differentiation have not been defined, and the precise role of the cytokines produced by gamma-delta T cells in vivo remains unknown. Our preliminary studies have demonstrated that gamma-delta T cells predominantly produce IFN-gamma upon activation, and the mechanisms that control gamma-delta T cell differentiation are different from CD4+ T cells. Furthermore, we have presented evidence that gamma-delta T cells play an important role in tumor immunity through their IFN-gamma production. Based on these data, we hypothesize that the molecular mechanisms for gamma-delta T cell differentiation, especially the factors that modulate gamma-delta T cell IFN-gamma secretion, are fundamentally different from those in alpha-beta CD4+ T cells. Moreover, we hypothesize that gamma-delta T cells play important roles in tumor immunity and in regulating the adaptive immune response (CD4+ and CD8+ T cell function) through their predominant production of IFN-gamma. To address these hypotheses, three specific aims are planned. First, delineation of the molecular mechanisms that control cytokine secretion by gamma-delta T cells. Here we will dissect the molecular mechanisms leading to IFN-gamma and IL-4 production by splenic gamma-delta T cells, focusing upon the different signaling pathways that have been well-studied in alpha-beta CD4+ T cells. Second, the role of gamma-delta T cells in tumor immunity in vivo through IFN-gamma production will be investigated. Here, we will use reconstituted mice in which T cell composition is intact except the ability of gamma-delta T cells to produce IFN-gamma allowing us to define the role of IFN-gamma produced by gamma-delta T cells in protective tumor response and the mechanisms. Finally, we will determine the roles of gamma-delta T cells in regulating the adaptive immune response using ovalbumin protein or peptide immunization system, to define the role of gamma-delta T cells in the development of antigen-specific CD4+ and CD8+ T cell effector function.

描述（由申请人提供）：与α - β T细胞相比，γ - δ T细胞具有独特的特征。现在已经很清楚，γ - δ T细胞识别非肽和未经加工的细菌和环境抗原，以及上皮和原发性癌上表达的应激相关抗原。体外和体内研究都表明，γ - δ T细胞可以分化为产生ifn - γ （th1样）和IL-4 （th2样）的细胞。然而，这种分化的分子机制尚未明确，γ - δ T细胞产生的细胞因子在体内的确切作用仍然未知。我们的初步研究表明，γ - δ T细胞在激活后主要产生ifn - γ，并且控制γ - δ T细胞分化的机制与CD4+ T细胞不同。此外，我们已经提出证据表明γ - δ T细胞通过其ifn - γ的产生在肿瘤免疫中发挥重要作用。基于这些数据，我们假设γ - δ T细胞分化的分子机制，特别是调节γ - δ T细胞ifn - γ分泌的因素，与α - β CD4+ T细胞的分子机制存在根本差异。此外，我们假设γ - δ T细胞通过主要产生ifn - γ在肿瘤免疫和调节适应性免疫反应（CD4+和CD8+ T细胞功能）中发挥重要作用。为了解决这些假设，计划了三个具体目标。首先，描述控制γ - δ T细胞分泌细胞因子的分子机制。在这里，我们将剖析脾脏γ - δ T细胞产生ifn - γ和IL-4的分子机制，重点关注已在α - β CD4+ T细胞中得到充分研究的不同信号通路。其次，将研究γ - δ T细胞通过产生ifn - γ在体内肿瘤免疫中的作用。在这里，我们将使用重组小鼠，其中T细胞成分是完整的，除了γ - δ T细胞产生ifn - γ的能力，使我们能够定义γ - δ T细胞产生的ifn - γ在保护性肿瘤反应中的作用及其机制。最后，我们将利用卵清蛋白或肽免疫系统确定γ - δ T细胞在调节适应性免疫反应中的作用，以确定γ - δ T细胞在抗原特异性CD4+和CD8+ T细胞效应功能发展中的作用。