Generation of antigen-specific regulation T cells

耐受的主要机制对自身免疫的干预具有明显的治疗意义 以及移植排斥反应。我们对“调节性”T(Treg)细胞如何被诱导及其模式的了解 作用在很大程度上源于对多克隆T细胞反应的研究。细胞的确切性质 调控调节性T细胞生成和动态平衡的相互作用仍然难以捉摸，而且 本提案的主题。我们将使用两个共享MHC的双转基因模型 针对流感血凝素(HA)的第二类限制性T细胞受体(TCR)，而模式抗原 HA在一个系统中以相当普遍的方式表达，在另一个系统中以组织特异性的方式表达。 在这两种模型中，我们都观察到“无能”的CD4T细胞可以抑制天然的CD4T细胞的反应 体外培养的细胞。TCR转基因CD4T细胞的调节特性与其表达的关系 CD25只在一个系统中存在，而在另一个系统中，CD25阴性细胞同样具有抑制作用。有趣的是， 胸腺上皮不仅在参与调节细胞生成的情况下广泛存在 抗原表达，但同样地，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“杂乱”表达。两者都有 转基因系统将被使用，并就造血和 胸腺上皮细胞在Treg细胞生成中的作用 胸腺来源的Treg细胞退出胸腺后的抗原依赖性。此外，我们还将测试 假设胸腺上皮细胞中所谓的组织抗原的“异位”表达参与了 Treg细胞的产生。最终，根据我们转基因系统中的观察结果，我们将测试 不同的实验方案在体内诱导Treg细胞。

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 na'fve 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 lifferent protocols to experimentally induce Treg cells in vivo.