GM-CSF Programs Alveolar Macrophages to Maintain Pulmonary Lymphocyte Homeostasis
Arumugam, P.; Guo, M.; Williams, C.; Carey, B.; Wessendarp, M.; Stock, J.; Jackson, D. L.; Read, D. F.; Mantilla, M.; Kumaragurubaran, R.; Suzuki, T.; Waterer, G.; Trapnell, C.; Trapnell, B.
Show abstract
Pulmonary lymphocytosis is a common feature of chronic lung disease, but the mechanisms governing lymphocyte accumulation within the lung remain poorly understood. Here, we identify granulocyte-macrophage colony-stimulating factor (GM-CSF) as a central regulator of pulmonary lymphocyte homeostasis. Using genetic models, single-nucleus and spatial transcriptomics, cell trafficking analyses, and pulmonary macrophage replacement studies, we show that loss of GM-CSF signaling causes profound pulmonary lymphocytosis characterized by lymphoid follicle formation, local immunoglobulin production, and expansion of multiple lymphocyte lineages. Mechanistically, GM-CSF signaling deficiency blocks terminal alveolar macrophage differentiation and reprograms alveolar macrophages into inflammatory states marked by reduced PU.1 and PPAR{gamma} expression, enhanced NF-{kappa}B signaling, and expression of lymphocyte-recruiting chemokines. These changes promote lymphocyte recruitment, local proliferation, and lymphoid lineage commitment. Restoration of GM-CSF-responsive alveolar macrophages re-established macrophage identity, suppressed inflammatory chemokine programs, and reversed pulmonary lymphocytosis. Together, these findings identify alveolar macrophages as gatekeepers of adaptive immune homeostasis in the lung.
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