Role of Innate lymphoid cells (ILC) and aryl hydrocarbon receptor (AhR) during pulmonary bacterial infections

铜绿假单胞菌（P.aer）引起的肺部疾病是住院和死亡的一个主要原因，特别是在免疫功能低下的个体和囊性纤维化患者中。P.aer气管内感染可用于研究急性免疫反应和炎症反应，炎症反应主要由先天免疫系统，特别是中性粒细胞介导，在96 h内自行消退，细菌完全清除。IL-17反应据称有助于中性粒细胞招募和对P.aer的抗性；然而，这种细胞因子的来源以及肺先天淋巴样细胞（ILCs）在P.aer感染中的作用尚不清楚。S. Kaufmann（该项目的第一个资助期的共同负责人）已经证明芳烃受体（AhR）作为P.aer色素毒力因子的识别传感器，AhR信号的损伤会影响体内感染期间的细菌负荷、宿主存活和组织损伤。然而，导致这种效应的免疫学机制才刚刚开始被阐明。由于AhR信号在调节T细胞和ilc的分化和功能中起着至关重要的作用，我们旨在研究AhR信号和ilc在P.aer感染中的作用。在之前的资助期内，我们描述了体内气管内感染P.aer后的ILC反应，并评估了不同淋巴细胞系中条件AhR缺失的影响。我们可以证明肺ILC3和NKp46+ ILCs细胞在体内感染P.aer时都被激活。然而，尽管RORt依赖性淋巴细胞（包括ILC3）对于生存是必不可少的，但NKp46+ ilc中AhR信号的选择性缺失对P.aer感染后的晚期生存和病程有严重影响。基于这些数据，我们假设NKp46+ ILC可能在P.aer感染后的免疫病理后期调节中发挥作用。为了验证这一假设，在下一个资助期，我们的目标是揭示NKp46+ ILCs在P.aer感染中的作用，并定义这些细胞中由AhR信号建立的细胞内在特征。该项目将使我们能够揭示ilc在肺部细菌感染中的作用，并可能有助于确定急性炎症和组织损伤调节的新靶点。

Pulmonary diseases caused by Pseudomonas aeruginosa (P.aer) represent one major cause of hospitalization and mortality, especially in immunocompromised individuals and in patients affected by cystic fibrosis. Intratracheal infection with P.aer can be used to study the acute immune response and inflammation, which is mainly mediated by the innate immune system, especially neutrophils, and spontaneously resolved within 96 h, together with complete bacterial clearance. IL-17 responses allegedly contribute to neutrophil recruitment and resistance against P.aer; however the sources of this cytokine as well as the role of lung innate lymphoid cells (ILCs) during P.aer infection remain unclear. S. Kaufmann (the Co-PI of this project during the first funding period) had shown that the aryl hydrocarbon receptor (AhR) acts as a recognition sensor for pigmented virulence factors from P.aer, and that impairment in AhR signalling affects bacterial load, host survival and tissue damage during in vivo infection. However, the immunological mechanisms responsible for this effect have only started to be elucidated. As AhR signalling is crucial in modulating differentiation and functions of T cells and ILCs, we aimed to investigate the role of AhR signalling and ILCs during P.aer infection.In the previous funding period, we have characterized ILC responses after in vivo intratracheal infection with P.aer and assessed the impact of conditional AhR deletion in different lymphocyte lineages. We could show that lung ILC3 and NKp46+ ILCs cells are both activated during in vivo infection with P.aer. However, while RORt-dependent lymphocytes, including ILC3, are dispensable for survival, selective deletion of AhR signalling in NKp46+ ILCs has a severe impact in the late survival and disease course after P.aer infection.Based on this data, we hypothesised that NKp46+ ILC may play a role in the late regulation of immunopathology, following P.aer infection. To test this hypothesis, in the next funding period, we aim to uncover the role of NKp46+ ILCs during P.aer infection and define the cell intrinsic signatures established by AhR signalling in these cells. This project will enable us unveiling the understudied role of ILCs during pulmonary bacterial infections and possibly help to identify new targets for the modulation of acute inflammation and tissue damage.