Regulatory T Cells Through the Indirect Pathway

通过间接途径调节 T 细胞

• 批准号: 7000419
• 负责人: A BENEDICT COSIMI
• 金额: $ 33.79万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7000419
• 关键词: Regulatory; Cells; Through; Indirect; Pathway

DESCRIPTION (provided by applicant): Regulatory T cells contribute to the prolonged survival of allogeneic tissues under some conditions. Many investigators have characterized regulatory cells by their phenotypic markers (such as CD4+CD25+) and others have tried to determine the mechanisms by which they work. In studies of allogeneic cardiac transplantation in mice using costimulatory blockade, we found that prolonged survival could not be achieved in recipients that lacked MHC class II molecules. This suggested that regulatory T cells might be generated through the indirect pathway. We have now accumulated additional preliminary data, using an adoptive transfer system, indicating that donor-specific CD4+CD25+ regulatory cells are specific for indirect determinants. In addition, the data are consistent with a model in which: 1) Peptides of donor MHC antigens are primarily responsible for generating the indirect determinants for this regulatory population, which functions by preventing activation of donor-reactive lymphocytes in secondary lymphoid organs. 2) An additional population of self-specific, CD4+ regulatory T cells is also be generated that can prevent the effector function of donor-reactive lymphocytes, but not their activation, if the self-determinant is expressed in the donor graft. 3) CD8+ cells alter the regulatory response, perhaps by producing additional populations of regulatory T cells. The experiments proposed in this application will focus on the specificity of regulatory T cells in transplantation, which will enable us to separate distinct subpopulations of these cells. We will test our proposed model by pursuing three specific aims that examine the different regulatory T cell subpopulations. The experiments in the fourth specific aim will use the information about their specificity to compare mechanistic properties of the regulatory T cell subpopulations and to develop diagnostic assays to detect their presence.

描述（由申请人提供）：调节性T细胞在某些条件下有助于同种异体组织的长期存活。许多研究者通过其表型标记（例如CD4+CD25+）来表征调节细胞，而其他研究人员则试图确定其工作机制。在使用共刺激阻滞的小鼠中同种异体心脏移植的研究中，我们发现缺乏MHC II类分子的受体无法实现延长的生存率。这表明调节T细胞可能是通过间接途径产生的。现在，我们使用收养转移系统积累了额外的初步数据，表明供体特异性的CD4+ CD25+调节细胞针对间接决定因素特异性。此外，数据与以下模型一致：1）供体MHC抗原的肽主要负责该调节群体的间接决定因素，该决定因素通过防止供体反应性淋巴细胞在次级淋巴机构中的激活而起作用。 2）还会产生额外的自我特异性CD4+调节T细胞，以防止供体反应性淋巴细胞的效应子功能，但不会激活，如果在供体移植中表达了自决的淋巴细胞。 3）CD8+细胞改变调节反应，也许是通过产生其他调节性T细胞种群的方法。本应用程序中提出的实验将集中于移植中调节T细胞的特异性，这将使我们能够分离这些细胞的不同亚群。我们将通过追求研究不同调节性T细胞亚群的三个特定目标来测试我们提出的模型。第四个特定目标中的实验将使用有关其特异性的信息来比较调节性T细胞亚群的机理特性，并开发诊断测定以检测其存在。