Lung vascular ILC3 subpopulation in anti-bacteria immunity and vasculature regeneration

Project Summary Pneumonia is the only infectious disease in the top ten causes of death in the United States. Bacterial pneumonia, such as Pseudomonas aeruginosa, induces massive inflammation and vascular damage in the lung. Therefore, a robust immune response is crucial for the protection and recovery of the lung when the infection occurs. Group 3 innate lymphoid cells (ILC3s) are emerging as a rapid responder to pathogen invasion in tissues including the lungs. However, how ILC3s invoke immune responses remains poorly understood. This application, by two PIs with complementary expertise, seeks to address the issue through combining innovative mouse models, single cell analysis, 3-D tissue imaging and in vitro assays. Our preliminary findings suggest that a novel ILC3 subpopulation is localized in the intravascular space of blood vessels (vILC3s) in contrast to the conventional parenchymal tissue ILC3s (tILC3s). While ablation of both ILC3 subsets causes defects in the clearance of P. aeruginosa, vILC3s exhibit distinct functions from tILC3s. For example, vILC3s produce the chemokine CCL4, and neutralizing CCL4 results in decreased neutrophil recruitment. vILC3s also produce the cytokine macrophage colony stimulating factor 1 (CSF1). Depletion of ILC3s including vILC3s causes impaired vasculature regeneration accompanied by reduced macrophage accumulation. We therefore hypothesize that vILC3s are important for bacterial clearance by facilitating neutrophil recruitment, and that vILC3s regulate vasculature regeneration by modulating macrophage function. Three specific aims are formulated to test the hypothesis: (1) define the tissue niche and response dynamics of lung vILC3s; (2) test the hypothesis that vILC3s mediate neutrophil recruitment for P. aeruginosa clearance; and (3) test the hypothesis that vILC3s promote vasculature regeneration through macrophage expansion. By integrating our expertise in mouse genetics, immunology, lung regeneration and epigenomics, this research will uncover novel mechanistic insights into tissue responses to bacterial pathogens, paving the way for new strategies to protect the lungs during infection.