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结果，可抑制对自身和非自身抗原（Ags）的有害免疫反应。免疫耐受受损可表现为过敏性或自身免疫性疾病。在吸入银诱导的小鼠耐受性模型中，我们先前发现表达Foxp3和膜结合TGF-¿（mTGF-¿）的调节性T细胞（Tregs）可以功能性地抑制银诱导的过敏性气道炎症。我们还证明mTGF-¿和Notch1之间的串扰是诱导耐受性的一种机制。随着目前适应性/诱导Treg （iTregs）和对外来Ags的感染耐受的概念，我们已经开始研究iTregs的产生，以了解如何增强和稳定Treg的功能。将Foxp3报告小鼠与CD11c- dtr小鼠结合，在CD11c细胞上表达白喉毒素受体，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诱导。在Tregs参与控制过敏性疾病的其他研究中，我们发现维生素D3在过敏性支气管肺曲霉病（ABPA）中促进mTGF-¿细胞的作用。鉴于目前对vit D3在调节过敏性疾病中的作用感兴趣，但对vit D受体（VDR）介导的效应如何引起免疫抑制知之甚少，我们建议使用转基因小鼠来研究vit D在Foxp3-与表达cd11c的细胞在iTreg生成中的作用。最后，正如本资助的前一个周期所提出的，我们已经成功地产生了表达Notch1下游靶点Hes1的CD4 T细胞特异性诱导转基因小鼠。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，特别是在炎症的背景下，这损害了Treg的功能。我们对这一提议的总体假设是：吸入Ag诱导Treg涉及dc的一个子集，并且该过程可以通过VDR-和Notch1/Hes1途径增强和稳定。为了解决这一假设，我们将：目的一：确定肺中诱导iTregs响应Ag的特定DC亚群。目的二世。探讨维生素D和VDR在Foxp3+ Tregs与CD11c+细胞促进吸入耐受中的作用。第三目标。研究Notch1的下游靶点Hes1在CD4+ T细胞中诱导表达，稳定和保持气道炎症小鼠肺中Treg功能的能力。

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.