Generation of antigen-specific regulation T cells

描述（由申请人提供）：耐受性的主要机制在干预自身免疫和移植排斥反应方面具有明显的治疗意义。我们对“调节性”T细胞（Treg）如何被诱导及其作用模式的了解主要来源于对多克隆T细胞反应的研究。控制调节性T细胞产生和稳态的细胞相互作用的确切性质仍然难以捉摸，是本提案的主题。我们将使用两种双转基因模型，它们共享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在一个系统中普遍表达，而在另一个系统中以“组织特异性”方式表达。在这两种模型中，我们都观察到“无能”CD4 T细胞可以在体外抑制初始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，而在其他CD25阴性细胞中同样具有抑制作用。有趣的是，胸腺上皮不仅在抗原广泛表达的情况下参与调节性细胞的产生，而且当抗原表达由“组织特异性”启动子驱动时也参与调节性细胞的产生，后者让人想起胸腺上皮细胞中组织抗原的“混杂”表达。这两种转基因系统将被采用并比较造血细胞和胸腺上皮细胞在Treg细胞产生中的作用，并解决有关胸腺来源的Treg细胞在离开胸腺后抗原依赖性的问题。此外，我们将验证胸腺上皮中所谓组织抗原的“混杂”表达参与Treg细胞产生的假设。最后，基于我们在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.