Generation of antigen-specific regulation T cells

免疫学！由表达FoxpS的调节性T细胞介导的耐受具有明显的治疗作用， 用于干预自身免疫、移植排斥和过敏。近年来 在了解Treg上抗原特异性受体的作用方面取得了相当大的进展， Treg的胸腺内和胸腺外生成及其向抗原沉积的特定位点的募集。的 ATTER有助于有效抑制共募集的效应细胞。抗原特异性Treg在以下情况下产生： 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 不清楚皮质上皮细胞的配体表达和/或皮质上皮细胞的交叉呈递的程度。 造血细胞有助于Treg生成。此外，目前还不清楚表达调控是否 AIRE转录因子的作用。关于通过亚免疫原性递送产生Treg 外周淋巴组织中的TCR配体，目前尚不清楚在TCR转基因小鼠中获得的结果是否 可以外推到野生型小鼠并用于特异性抑制不需要的免疫应答。最后， 关于Treg介导的体内抑制的分子机制的信息非常少。在 为了更好地了解胸腺内Treg生成的过程及其可能的调节AIRE 转录因子，我们在目的1中提出，分析FoxpS表达的胸腺细胞的产生， 流感病毒血凝素（HA）肽107-119特异性转基因T细胞受体（TCR-HA）， 重新聚集胎儿胸腺器官培养物（RFTOC），其中皮质和髓质上皮细胞在其 能够诱导Treg的TCR配体的表达。在目标2中，我们提出特异性诱导Treg 目的是干预移植排斥、移植物抗宿主病和变态反应 通过探索将TCR转基因小鼠中获得的结果转化为野生型小鼠。目标3将处理 Treg中Foxp 3启动子结合与调控基因表达的相关性以及基因表达 分析调节与非调节的CD 8+效应细胞，目的是鉴定分子 调节Treg介导的T效应子功能抑制的机制。

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.