Mechanism of gamma-delta T cell differentiation

γ-δ T细胞分化机制

• 批准号: 6676278
• 负责人: ZHINAN YIN
• 金额: $ 32.7万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-15 至 2004-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6676278
• 关键词: CD14 molecule; JUN kinase; T cell receptor; T lymphocyte; biological signal transduction; cell differentiation; cellular polarity; cytokine; enzyme activity; enzyme linked immunosorbent assay; flow cytometry; genetic transcription; helper T lymphocyte; immunogenetics; interferon gamma; interleukin 4; laboratory mouse; leukocyte activation /transformation; mitogen activated protein kinase; neoplasm /cancer immunology; ovalbumin; receptor expression; secretion

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 (Th2-1ike)-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，以及在上皮和原发性癌上表达的应激相关抗原。体外和体内研究均表明，γ-δ T细胞可分化为产生IFN-γ（Th 1样）和IL-4（Th 2样）的细胞。然而，这种分化的分子机制尚未确定，γ-δ T细胞在体内产生的细胞因子的确切作用仍然未知。我们的初步研究表明，γ-δ T细胞主要产生IFN-γ激活后，和控制γ-δ T细胞分化的机制是从CD 4 + T细胞不同。此外，我们已经提出了证据表明，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分泌的因子，与α-β CD 4 + T细胞中的分子机制根本不同。此外，我们假设γ-δ T细胞在肿瘤免疫和通过其主要产生IFN-γ调节适应性免疫应答（CD 4+和CD 8 + 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，描绘控制γ-δ T细胞分泌细胞因子的分子机制。在这里，我们将剖析导致IFN-γ和IL-4生产的脾γ-δ T细胞的分子机制，专注于不同的信号通路，已在α-β CD 4 +T细胞研究。其次，将研究γ-δ T细胞通过IFN-γ产生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细胞组成是完整的，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和机制。最后，我们将使用卵清蛋白蛋白或肽免疫系统确定γ-δ T细胞在调节适应性免疫应答中的作用，以确定γ-δ T细胞在抗原特异性CD 4+和CD 8 + T细胞效应器功能发育中的作用。