Generation of antigen-specific regulation T cells

抗原特异性调节 T 细胞的产生

• 批准号: 6558064
• 负责人: HARALD VON BOEHMER
• 金额: $ 52.68万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6558064
• 关键词: B lymphocyte; CD antigens; T cell receptor; antigen presentation; antigen presenting cell; cell cell interaction; cell differentiation; dendritic cells; genetically modified animals; helper T lymphocyte; laboratory mouse; microorganism hemagglutinin; thymus

DESCRIPTION (provided by the applicant): Dominant mechanisms of tolerance have obvious therapeutic implications for intervention in autoimmunity and transplant-rejection. Our knowledge of how "regulatory" T (Treg) cells are induced and their mode of action is largely derived from studies of polyclonal T cell responses. The exact nature of the cellular interactions that govern the generation and homeostasis of regulatory T cells remains elusive and is subject of the present proposal. We will make use of two double-transgenic models that share an MHC class II restricted T cell receptor (TCR) specific for influenza hemagglutinin (HA), while the model antigen HA is expressed rather ubiquitously in one system and in a "tissue-specific" fashion in the other system. In both models, we have observed "anergic" CD4 T cells that can suppress the response of naive CD4 T cells in vitro. The regulatory properties of TCR transgenic CD4 T cells segregate with the expression of CD25 only in one system, while in the other CD25 negative cells are likewise inhibitory. Intriguingly, thymic epithelium is involved in the generation of regulatory cells not only in the situation of widespread antigen expression, but likewise when antigen expression is driven by a "tissue-specific" promoter, the latter being reminiscent of "promiscuous" expression of tissue-antigens in thymic epithelial cells. Both transgenic systems will be employed and compared with respect to the role of hematopoietic versus thymic epithelial cells in the generation of Treg cells and to address questions concerning the antigen-dependency of thymus derived Treg cells after exit from the thymus. Furthermore, we will test the hypothesis that "promiscuous" expression of so-called tissue-antigens in thymic epithelium is involved in the generation of Treg cells. Ultimately, based on the observations in our transgenic systems, we will test different protocols to experimentally induce Treg cells in vivo.

描述（由申请人提供）：耐受性的主要机制对自身免疫性和移植拒绝的干预具有明显的治疗意义。我们对如何诱导“调节” T（Treg）细胞的了解，其作用方式主要来自多克隆T细胞反应的研究。控制调节T细胞的产生和稳态的细胞相互作用的确切性质仍然难以捉摸，并且是本提案的主题。我们将利用两种双重转基因模型，它们共享针对流感的Hemagglutinin（HA）的MHC II类限制的T细胞受体（TCR），而模型抗原HA在一个系统中和另一个系统中的“组织特异性”方式中相当无处不在。在这两个模型中，我们都观察到“厌食” CD4 T细胞可以抑制幼稚的CD4 T细胞体外的反应。 TCR转基因CD4 T细胞的调节性能仅在一个系统中与CD25的表达分离，而在另一个CD25阴性细胞中也是抑制性的。有趣的是，胸腺上皮不仅参与了调节细胞的产生，不仅是在广泛的抗原表达的情况下，而且同样，当抗原表达受到“组织特异性”启动子的驱动，后者让人联想到甲状腺素抗原剂在胸膜上皮细胞中的“混乱”表达。两种转基因系统将被采用并就造血和胸皮上皮细胞在Treg细胞产生中的作用进行比较，并解决有关胸腺退出后胸腺衍生细胞的抗原依赖性的问题。此外，我们将检验以下假设：胸皮上皮中所谓的组织抗原的“混杂”表达参与Treg细胞的产生。最终，基于转基因系统中的观察结果，我们将测试不同方案，以实验诱导体内treg细胞。