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

摘要 肺是一个天然的致耐受性器官。肺粘膜耐受必须由肺精细地控制 免疫系统，以避免慢性炎症性肺部疾病的发展。我们对肺的认识 然而，宽容是不够的。这在哮喘治疗中很明显。目前的哮喘治疗仅限于 减缓疾病的发展一旦停止治疗，患者就会复发， 治疗不能修复潜在的失调的肺粘膜耐受性。肺树突状细胞 协调肺部免疫反应。我们最近报道了肺上皮细胞IFNβ-TNFR 2 + cDC 2（R2D2）- 肺耐受性的调节。我们进一步表明，肺R2D2细胞是可塑性的，这使得它们 治疗干预的理想目标。肺结核在维持耐受性中的重要作用一直是 牢固确立。在这个建议中，我们集中在i）揭示肺的分子和细胞机制 上皮细胞IFNβ-R2D2控制肺粘膜耐受; ii）开发基于IFNβ的方案以恢复 慢性炎症性肺病中的肺耐受性。我们的研究表明，肺泡II型细胞 （AT-II）是IFNβ+细胞，并且STING对于肺中的基础IFNβ产生是必需的。在AIM 1中，我们将 确定肺AT-II细胞维持肺IFNβ水平和维持肺耐受的体内机制 在稳定状态下。在Aim 2中，我们将确定小鼠和人肺R2 D2中的致耐受性IFNβ程序 细胞在目标3中，我们将开发一种基于IFNβ的方案，以增强、恢复肺耐受性，并预防、治疗 小鼠的炎症性肺病。慢性炎症性肺病是第四大死亡原因， 了解肺耐受的基本机制，并开发新的创新方案 恢复肺黏膜耐受在慢性肺部疾病中具有重要意义。

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.