Inter-organ programming of lung immunity across development and disease

The lung processes approximately 10,000 liters of air and its accompanying irritants, pathogens and environmental antigens every day. To maintain homeostasis, the lung must provide robust defense against harmful pathogens while maintaining tolerance towards harmless particulates in a challenging balancing act. This dissertation establishes that pulmonary immunity is dynamically shaped across the lifespan by signals from distant organs, a concept termed inter-organ programming. Using four distinct models, this research investigates how developmental, microbial, and systemic cues from the gut, skin and peripheral blood converge to dictate the lung’s immune setpoint and susceptibility to disease. The first model explores the gut-lung axis, demonstrating that early-life gut microbial perturbations trigger a transient surge in neonatal lung basophils. This event is associated with a sexually dimorphic loss of epithelial barrier integrity and impaired alveolar macrophage maturation, which reshapes the lung landscape and increases susceptibility to allergic asthma in adulthood. The second model examines the plasticity of the pulmonary lymphoid compartment. We show that inflammation drives unconventional T cells to downregulate surface markers and adopt a convergent transcriptional program that mimics innate lymphoid cells (ILCs). This finding highlights how the inflamed lung can drive different cell lineages towards a shared pathological phenotype. The third model characterizes the skin-lung axis, showing that skin barrier disruption induces systemic inflammation that primes lung ILC2 and neutrophils, potentially reflecting an evolutionary defense mechanism where a skin barrier breach preemptively strengthens pulmonary defenses. Finally, we identify circulating blood biomarkers of fibrosis in a human interstitial lung disease cohort. We find that blood immune signatures, such as double negative αβ T cells and serum CCL13, communicate lung impairment and provide a minimally invasive window into interstitial lung disease. Collectively, we reveal that the lung’s immune setpoint is a product of systemic crosstalk. By demonstrating that the gut’s microbiome provides developmental cues, the skin’s integrity initiates protective priming and the blood’s cellular composition reflects internal organ damage, this dissertation offers a systems-wide framework of respiratory health. This work prompts us to consider moving beyond an organ-centric approach and consider the broader systemic landscape to approach and treat chronic lung disease.