Mechanisms of Antigen Induced Tolerance in the Lung

描述(由申请人提供)：外周T细胞耐受是一种重要的免疫学结果，它抑制对自身和非自身抗原(AGS)的有害免疫反应。免疫耐受性受损可表现为过敏性或自身免疫性疾病。在吸入Ag诱导的小鼠耐受模型中，我们先前发现表达Foxp3和膜结合的转化生长因子-β(mTGF-β)的调节性T细胞(Tregs)在功能上抑制了由Ag诱导的过敏性气道炎症。我们还证明了mTGF-β和Notch1之间的串扰是诱导耐受的一种机制。随着目前适应性/诱导Tregs(ITregs)和对外来AGS的感染耐受的概念的提出，我们已经开始研究iTregs的产生，更大的目标是了解Treg的功能如何被增强和稳定。使用Foxp3报告小鼠和表达CD11c细胞上白喉毒素受体的CD11c-DTR小鼠，我们建立了一个系统来确定哪些树突状细胞(DC)亚群参与iTreg的诱导。在其他关于Tregs参与控制过敏性疾病的研究中，我们发现维生素D3在过敏性支气管肺曲霉菌病(ABPA)背景下促进mTGF-β细胞的作用。鉴于目前对维生素D3在调节变态反应性疾病方面的兴趣，而对维生素D受体(VDR)介导的效应如何导致免疫抑制知之甚少，我们建议使用转基因小鼠来研究维生素D在Foxp3与CD11c表达细胞在iTreg生成中的作用。最后，正如这项资助的前一个周期所建议的那样，我们已经成功地产生了一只CD4T细胞特异的可诱导转基因小鼠，表达Notch1的下游靶标Hes1。这只小鼠的产生是为了了解Hes1在Treg介导的免疫抑制中的作用，特别是在影响Treg功能的炎症背景下。我们对这一提议的总体假设是：吸入Ag诱导的Treg涉及DC的一个子集，这一过程可以通过VDR-和Notch1/Hes1途径得到增强和稳定。为了解决这一假设，我们将：目标1.确定肺中诱导iTregs对Ag反应的特定DC亚群。目的II.探讨维生素D和VDR在Foxp3+Tregs和CD11c+细胞促进吸入耐受中的作用。目的III.研究Notch1的下游靶点Hes1以诱导方式在CD4+T细胞中表达的能力，以稳定和保护呼吸道炎症小鼠肺中的Treg功能。 公共卫生相关性：这项应用的目标是了解调节性T细胞是如何在肺内诱导的，以响应变应原，以及如何增强和稳定它们的抑制功能。

DESCRIPTION (provided by applicant): Peripheral T cell tolerance is an important immunological outcome that inhibits deleterious immune responses to both self and non-self antigens (Ags). Impaired immune tolerance can manifest as either allergic or autoimmune disease. In a murine model of tolerance induced by inhaled Ag, we previously identified regulatory T cells (Tregs) expressing Foxp3 and membrane-bound TGF-¿ (mTGF-¿) that functionally suppressed allergic airway inflammation induced by the Ag. We also demonstrated cross-talk between mTGF-¿ and Notch1 as one mechanism of induced tolerance. With the current concepts of adaptive/induced Tregs (iTregs) and infectious tolerance elicited in response to foreign Ags, we have initiated studies to examine generation of iTregs with a bigger goal of understanding how the function of a Treg can be enhanced and stabilized. Using Foxp3 reporter mice in conjunction with CD11c-DTR mice that express the diphtheria toxin receptor on CD11c cells, we have established a system to determine which dendritic cell (DC) subsets contribute to iTreg induction. In other studies of involvement of Tregs in controlling allergic disease, we have found a role for vitamin D3 in promoting mTGF-¿ cells in the context of allergic bronchopulmonary aspergillosis (ABPA). Given the current interest in vit D3 in regulating allergic diseases with little understanding of how vit D receptor (VDR)-mediated effects cause immunosuppression, we propose to use genetically altered mice to investigate the role of vit D in Foxp3- versus CD11c-expressing cells in iTreg generation. Finally, as proposed in the previous cycle of this grant, we have successfully generated a CD4 T cell-specific inducible transgenic mouse expressing Hes1, a downstream target of Notch1. This mouse was generated to understand the role of Hes1 in Treg-mediated immunosuppression, particularly in the context of inflammation, which compromises Treg function. Our overall hypothesis for this proposal is: Treg induction by inhaled Ag involves a subset of DCs and the process can be enhanced and stabilized by VDR- and Notch1/Hes1 pathways. To address this hypothesis we will: Aim I. Identify the specific DC subsets in the lung that induce iTregs in response to Ag. Aim II. Investigate the involvement of vitamin D and VDR in Foxp3+ Tregs versus CD11c+ cells in promoting inhaled tolerance. Aim III. Study the ability of Hes1, a downstream target of Notch1, expressed in an inducible fashion in CD4+ T cells, to stabilize and preserve Treg function in the lungs of mice subjected to airway inflammation. PUBLIC HEALTH RELEVANCE: The goal of this application is to understand how regulatory T cells are induced in the lung in response to allergens and how their suppressive function can be enhanced and stabilized.