Tolerance to epidermal antigens

朗格汉斯细胞是一种树突状细胞，在屏障的免疫中发挥重要作用。 表面。它们在皮肤复层上皮的底部形成一个网络。他们有强大的抗原性 在体外呈现功能，并在体内促进强大的免疫反应，正如我们在之前的 资助期。然而，它们也被认为在耐受和免疫抑制方面发挥作用， 尤其是在低剂量UVB照射后。朗格汉斯细胞在脑内的作用也引起了越来越多的兴趣。 皮肤表面免疫，这是一种对病毒和细菌感染显示出惊人疗效的策略，以及 肿瘤。尽管如此，朗格汉斯细胞的许多基本特性目前尚不清楚：包括 它们是否能交叉呈递MHCClass I抗原，如果它们能诱导外周耐受，以及它们如何 皮肤受到侮辱或损伤后，免疫学特性会发生变化。幸运的是，这一领域正在迅速 开发精辟的工具来研究这一群体。在当前的应用程序中，我们建议使用一些 这些新工具和开发的其他工具，将使我们能够回答关于 郎格汉斯细胞(LC)在外周皮肤抗原耐受中的作用我们建议创建和研究TCR 天然表皮抗原酪氨酸酶相关蛋白2的高亲和力和低亲和力转基因 (Trp2)。我们将使用骨骼定义负责处理和呈现trp2180-188的ARC 骨髓嵌合体和诱导性LC缺陷小鼠。我们还将研究朗格汉斯细胞在耐受中的作用 和对通过皮肤引入的外源抗原的免疫力(皮肤表面免疫或ECI) 开发基于卵清蛋白的模型系统。利用这一点，我们将能够测试关于 皮肤免疫反应调节剂咪喹莫特、CpG DNA和UVB辐射如何影响免疫和 宽容。

Langerhans cells are a type of dendritic cell uniquely positioned to play a vital role in immunity at the barrier surfaces. They form a network at the base of stratified epithelium in the skin. They have potent antigen presenting function in vitro, and promote robust immune responses in vivo, as we showed in the previous funding period. However, they are also thought to play a role in tolerance and immunological suppression, particularly after low dose UVB irradiation. There is also growing interest in the role of Langerhans cells in epicutaneous immunization, a strategy that shows surprising efficacy against viral and bacterial infection, and tumors. Nonetheless/many basic properties of Langerhans cells are uncharacterized at present: including whether they can cross-present MHCClass I antigens, if they can induce peripheral tolerance, and how their immunological properties are changed after insult or injury to the skin. Fortunately, the field is rapidly developing incisive tools to study this population. In the current application we propose to utilize someof these new tools and develop others, that together will allow us to answer specific questions about the role of Langerhans cells (LC) in peripheral tolerance to epidermal antigens. We propose to create and study TCR transgenics with high and low affinity for a naturally occurring epidermal antigen: tryosinase related protein 2 (trp2). We will define the ARC responsible for processing and presentation of trp2180-188, using bone marrow chimeras and inducibly LC deficient mice. We will also study the role of Langerhans cells in tolerance and immunity to exogenousantigens introduced through the skin (epicutaneous immunization or ECI) by developing an ovalbumin-based model system. Using this we will be able to test specific hypotheses about how skin immune response modifiers, Imiquimod, CPG DNA, and UVB irradiation, influence immunity and tolerance.