Lung IDO-1+ TNFR2+ cDC2 subset in control of lung mucosal tolerance: Mechanism and Application

摘要 肺是一种天然的耐受器官。肺粘膜耐受性必须由肺精确控制 免疫系统避免发展为慢性炎症性肺部疾病。我们对肺的认识 然而，容忍是不够的。这一点在哮喘治疗中很明显。目前哮喘的治疗方法仅限于 阻碍了疾病的发展。一旦停止治疗，患者就会复发，因为 治疗不会修复潜在的、失调的肺粘膜耐受性。肺树突状细胞(DC) 协调肺部免疫反应。我们最近报道了一种肺上皮细胞干扰素β-TnFR2+CDC2(R2D2)- Tregs轴在控制肺耐受中的作用。我们进一步证明，肺R2D2细胞是可塑性的，这使得它们 是治疗干预的理想靶点。肺树在维持耐受中的重要作用一直是 站稳了脚跟。在这项建议中，我们的重点是：1)揭示肺的分子和细胞机制 上皮细胞干扰素β-R2D2控制肺粘膜耐受性；ii)开发基于干扰素β的方案以恢复 慢性炎症性肺病患者的肺耐受性。在这项研究中，我们发现肺泡II型细胞 (AT-II)是干扰素β+细胞，而刺痛对于肺内基础干扰素β的产生是必不可少的。在Aim1，我们将 肺AT-II细胞维持肺干扰素β水平和维持肺耐受的体内机制 在稳定状态下。在AIM2中，我们将确定在小鼠和人肺R2D2中产生耐受性的干扰素β程序 细胞。在AIM3中，我们将开发一种基于干扰素β的方案来增强、恢复肺耐受，并预防、治疗 小鼠肺部炎症性疾病。慢性炎症性肺部疾病是#年的第四大死因。 美国了解肺耐受的基本机制并开发新的创新疗法 恢复慢性肺病患者的肺粘膜耐受性具有重要意义。

Abstract The lung is a natural tolerogenic organ. Lung mucosal tolerance must be exquisitely controlled by the lung immune system to avoid the development of chronic inflammatory lung diseases. Our knowledge of lung tolerance is, however, inadequate. This is evident in asthma treatments. Current asthma therapies are limited to blunting the progression of the disease. Patients relapse once the treatments are stopped because the treatments do not repair the underlying, dysregulated lung mucosal tolerance. Lung dendritic cells (DCs) orchestrate lung immune responses. We recently reported a lung epithelial cells IFNβ-TNFR2+ cDC2 (R2D2) - Tregs axis in control of lung tolerance. We further showed that lung R2D2 cells are plastic, which makes them an ideal target for therapeutic intervention. The essential role of lung Tregs in maintaining tolerance has been firmly established. In this proposal, we focus on i) uncovering the molecular and cellular mechanisms of the lung epithelial cells IFNβ-R2D2 control of lung mucosal tolerance; ii) developing an IFNβ-based regimen to restore lung tolerance in chronic inflammatory lung diseases. We showed, in this proposal, that lung alveolar type II cells (AT-II) are the IFNβ+ cells, and STING is essential for basal IFNβ production in the lung. In Aim1, we will determine the in vivo mechanism by which lung AT-II cells sustain lung IFNβ level and maintain lung tolerance at the steady-state. In Aim2, we will determine the tolerogenic IFNβ program in mouse and human lung R2D2 cells. In Aim3, we will develop an IFNβ-based regimen to enhance, restore lung tolerance, and prevent, treat inflammatory lung diseases in mice. Chronic inflammatory lung diseases are the 4th leading cause of death in the U.S. Understanding the fundamental mechanism for lung tolerance and develop a new innovative regimen to restore lung mucosal tolerance in chronic lung diseases are highly significant.