Generation of antigen-specific regulation T cells

免疫学！FoxpS表达的调节性T细胞介导的耐受具有明显的治疗作用 干预自身免疫、移植排斥和过敏的三联药物。近年来，我们看到了 在了解抗原特异性受体在Treg上的作用方面取得了相当大的进展 NTRA和胸腺外生成Treg，并将其募集到特定的抗原沉积部位。这个 ATER有助于有效抑制共招募的效应细胞。抗原特异性Treg在以下情况下生成 发育中的胸腺细胞的TCR与胸腺上皮细胞表达的同源TCR配体结合，但它 尚不清楚皮质上皮细胞在多大程度上表达配体和/或通过 造血细胞参与Treg的生成。此外，目前还不清楚对表达的调控 通过AIRE转录因子可以起到作用。关于亚免疫原性递送产生Treg TCR转基因小鼠外周淋巴组织中TCR配体的检测结果尚不清楚 可以外推到wt小鼠，并被利用来专门抑制不想要的免疫反应。最后， 目前对Treg介导的体内抑制的分子机制知之甚少。在……里面 为了更好地了解Treg生成的胸腺内过程以及AIRE对其可能的调节 转录因子，我们在目标1中建议分析表达FoxpS的胸腺细胞的生成。 抗流感血凝素107-119肽的转基因T细胞受体(TCR-HA)的构建 重组胎儿胸腺器官培养(RFTOC)中皮质和髓质上皮细胞的差异 能够诱导Treg的TCR配体的表达。在目标2中，我们建议诱导具有特异性的Treg 对于目标是干预移植排斥反应、移植物抗宿主疾病和过敏的外来配体 通过探索将在TCR转基因小鼠中获得的结果转化为wt小鼠。AIM 3将处理 Foxp3启动子结合与Treg基因表达调控的相关性 分析调节性和非调节性CD8+效应细胞，目的是鉴定分子 Treg介导的抑制T效应功能的机制。

Immunologies! tolerance that is mediated by FoxpS-expressingregulatory T cells has obvious therapeutic triplications for intervention in autoimmunity, transplant rejection and allergy. Recent years have seen considerable progress in understanding the role of antigen-specific receptors on Treg that are involved in ntra- and extra-thymic generation of Treg and their recruitment to specific sites of antigen deposition. The atter facilitates effective suppression of co-recruited effector cells. Antigen-specific Treg are generated when the TCR of developing thymocytes binds to cognate TCR-ligands expressed by thymic epithelial cells, but it is not clear to what extent expression of ligands by cortical epithelial cells and/or cross-presentation by hemopoietic cells contribute to Treg generation. Furthermore, it is unclear whether regulation of expression by the AIRE transcription factor can contribute. With regard to Treg generation by subimmunogenic delivery of TCR-ligands in peripheral lymphoid tissue, it is not clear whether results obtained in TCR transgenic mice can be extrapolated to wt mice and exploited to specifically suppress unwanted immune responses. Finally, there is very little information on molecular mechanisms involved in Treg-mediated suppression in vivo. In order to understand better the intrathymic process of Treg generation and its possible regulation by the AIRE transcription factor, we propose in Aim 1 to analyze the generation of FoxpS-expressingthymocytes with a transgenic T cell receptor (TCR-HA) specific for peptide 107-119 of influenza hemagglutinin (HA) in reaggregate fetal thymic organ cultures (RFTOC) in which cortical and medullary epithelial cells differ in their expression of TCR ligands that are able to induce Treg. In Aim 2 we propose to induce Treg with specificity for foreign ligands with the goal to intervene with transplant rejection, graft versus host disease and allergy by exploring the translation of results obtained in TCR transgenic mice into wt mice. Aim 3 will deal with the correlation of Foxp3 promoter binding and regulated gene expression in Treg as well as gene expression analysis in regulated versus non-regulated CD8+ effector cells with the goal to identify molecular mechanisms that govern Treg-mediated suppression of T effector function.