Tolerance to epidermal antigens

朗格汉斯细胞是一种树突状细胞，在屏障免疫中发挥重要作用 表面。它们在皮肤中的复层上皮的基部形成网络。它们有很强的抗原 在体外呈现功能，并在体内促进强大的免疫应答，正如我们在前面的文章中所展示的那样。 融资期。然而，它们也被认为在耐受性和免疫抑制中起作用， 特别是在低剂量UVB照射后。人们对郎格罕细胞在肿瘤发生中的作用也越来越感兴趣。 表皮免疫，一种对病毒和细菌感染显示出惊人功效的策略，以及 肿瘤的尽管如此，朗格汉斯细胞的许多基本特性目前还没有被表征： 它们是否可以交叉呈递MHC-I类抗原，是否可以诱导外周耐受，以及它们如何表达MHC-I类抗原。 免疫学特性在皮肤损伤或损伤后发生变化。幸运的是，该领域正在迅速 开发出了研究这一人群的精确工具。在本申请中，我们提出利用一些 这些新工具和开发其他工具，共同使我们能够回答有关 朗格汉斯细胞（LC）在外周耐受表皮抗原。我们建议创建和研究TCR 对天然存在的表皮抗原：酪氨酸酶相关蛋白2具有高和低亲和力的转基因 （trp 2）。我们将使用骨骼来定义负责处理和呈现trp 2180 -188的ARC。 骨髓嵌合体和可诱导的LC缺陷小鼠。我们还将研究朗格汉斯细胞在耐受中的作用 以及通过皮肤引入的对外源性抗原的免疫（表皮免疫或ECI）， 开发基于卵清蛋白的模型系统。利用这一点，我们将能够测试特定的假设， 皮肤免疫反应调节剂，咪喹莫特，CPG DNA和UVB照射如何影响免疫力， 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.