Generation of antigen-specific regulation T cells

描述（由申请方提供）：耐受性的主要机制对干预自身免疫和移植排斥具有明显的治疗意义。我们对“调节性”T（Treg）细胞如何被诱导及其作用模式的了解主要来自多克隆T细胞应答的研究。控制调节性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，并且是本提议的主题。我们将利用两个双转基因模型，共享一个MHC II类限制性T细胞受体（TCR）特异性流感血凝素（HA），而模型抗原HA的表达，而无处不在的一个系统和“组织特异性”的方式在其他系统。在这两种模型中，我们都观察到了“无反应性”的CD4 T细胞，它们可以抑制体外幼稚CD4 T细胞的反应。TCR转基因CD4 T细胞的调节特性仅在一个系统中与CD25的表达分离，而在另一个系统中CD25阴性细胞同样具有抑制性。有趣的是，胸腺上皮不仅在广泛抗原表达的情况下参与调节细胞的产生，而且同样地，当抗原表达由“组织特异性”启动子驱动时，后者使人联想到胸腺上皮细胞中组织抗原的“混杂”表达。将采用两种转基因系统，并就造血细胞与胸腺上皮细胞在Treg细胞生成中的作用进行比较，并解决有关胸腺来源的Treg细胞在离开胸腺后的抗原依赖性的问题。此外，我们将测试的假设，即所谓的组织抗原在胸腺上皮细胞中的“混杂”表达参与Treg细胞的产生。最终，基于我们的转基因系统中的观察，我们将测试不同的方案来实验性地在体内诱导Treg细胞。

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.