Behavior of regularity CD25+ CD4 T cells in vivo

体内规律性 CD25 CD4 T 细胞的行为

• 批准号: 7026397
• 负责人: ALEXANDER KHORUTS
• 金额: $ 35.08万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7026397
• 关键词: CD antigens; T cell receptor; antigen presentation; antigen presenting cell; autoantigens; autoimmunity; cell cell interaction; dendritic cells; genetically modified animals; helper T lymphocyte; immunoregulation; laboratory mouse; lymphopenia; lymphopoiesis

DESCRIPTION (provided by applicant): Regulatory CD25+CD4 T cells are important mediators of immunologic tolerance and are likely to become a therapeutic target. However, their mechanisms in vivo remain largely unknown, and are the main focus of this proposal. The summary of the preliminary work described here shows that 1) we are able to purify in numbers sufficient for the proposed experiments antigen-specific regulatory CD25+CD4 T cells from wild-type TCR Tg mice and antigen-specific regulatory CD25+CD4 T cells expressing a single known TCR; 2) we have established two complementary in vivo systems to measure suppressive effects of CD25+CD4 T cells on responder T cells in non-lymphopenic animals; 3) we are able to simultaneously visualize the behavior and cellular interactions of antigen-specific CD25+CD4 T cells, antigen-specific responder T cells, and antigen-presenting dendritic cells; 4) CD25+CD4 T cells reduce the size of the T cell population responding to antigen and inhibit production of effector Th1and Th2 cytokines; and 5) CD25+CD4 T cells inhibit homeostatic proliferation of naive T cells in lymphopenic mice. The laboratory is now exceptionally poised to pursue the two specific aims in the proposal. In the first aim we will define the cellular mechanisms of by which CD25+CD4 T cells inhibit the antigen-specific T cell responses within the secondary lymphoid tissues. We will determine the fates of the dendritic cells presenting the antigen as well the antigen-specific CD25+CD4 T cells and responder T cells. In the second aim we will determine how CD25+CD4 T cells shape the development of the T cell compartment during immune reconstitution by homeostatic proliferation. In particular, we will test how CD25+CD4 T cells may regulate potentially auto-aggressive T cell clones under conditions of lymphopenia. Although cellular mechanisms constitute the main focus of this proposal, the experimental systems described are robust and are ideally suited for testing roles of specific molecules in CD25+CD4 T cell-mediated immune regulation.

描述（由申请人提供）：调节性 CD25+CD4 T 细胞是免疫耐受的重要介质，并且可能成为治疗靶点。然而，它们的体内机制在很大程度上仍然未知，并且是该提案的主要焦点。这里描述的初步工作的总结表明1)我们能够从野生型TCR Tg小鼠和表达单一已知TCR的抗原特异性调节CD25+CD4 T细胞和抗原特异性调节CD25+CD4 T细胞中纯化出足够数量用于所提议的实验的抗原特异性调节CD25+CD4 T细胞； 2）我们建立了两个互补的体内系统来测量CD25+CD4 T细胞对非淋巴细胞减少动物中应答T细胞的抑制作用； 3) 我们能够同时可视化抗原特异性 CD25+CD4 T 细胞、抗原特异性应答 T 细胞和抗原呈递树突状细胞的行为和细胞相互作用； 4) CD25+CD4 T细胞减少响应抗原的T细胞群的大小并抑制效应Th1和Th2细胞因子的产生； 5) CD25+CD4 T 细胞抑制淋巴细胞减少小鼠中幼稚 T 细胞的稳态增殖。该实验室现在已准备好实现该提案中的两个具体目标。在第一个目标中，我们将定义 CD25+CD4 T 细胞抑制次级淋巴组织内抗原特异性 T 细胞反应的细胞机制。我们将确定呈递抗原的树突状细胞以及抗原特异性 CD25+CD4 T 细胞和应答 T 细胞的命运。在第二个目标中，我们将确定 CD25+CD4 T 细胞在通过稳态增殖进行免疫重建期间如何塑造 T 细胞区室的发育。特别是，我们将测试 CD25+CD4 T 细胞如何在淋巴细胞减少的情况下调节潜在的自身攻击性 T 细胞克隆。尽管细胞机制构成了该提案的主要焦点，但所描述的实验系统非常强大，非常适合测试特定分子在 CD25+CD4 T 细胞介导的免疫调节中的作用。