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AT2-Derived GM-CSF Promotes CD301b⁺ cDC2 Generation and Type 2 Inflammation in the Lung

ABSTRACT: Pulmonary conventional dendritic cells (cDCs) are functionally and phenotypically heterogeneous antigen-presenting cells essential for orchestrating adaptive immune responses in the lung. Here, we define a critical role for granulocyte-macrophage colony-stimulating factor (GM-CSF) in generating a CD301b+ subset of terminally differentiated cDC2s. GM-CSF signaling is intrinsically required for their development, independent of GM-CSF-dependent alveolar macrophages. Absence of GM-CSF results in a defect similar to that seen in CD103+XCR1+ cDC1s. Unbiased single-cell transcriptomic profiling of CD11c+ cells identified both immature and differentiated cDC populations. GM-CSF deficiency disrupted anti-apoptotic Bcl2a1 upregulation and impaired progression to the CD301b+ transcriptional state. Despite their positioning in lymphoid cell-rich adventitial cuff areas, hematopoietic GM-CSF was dispensable. Instead, genetic GM-CSF gain- and loss-of-function studies showed that alveolar epithelial type 2 cell-derived GM-CSF is required for CD301b+ cDC2 formation and pulmonary type 2 immune responses, highlighting the central role of GM-CSF signaling in shaping the pulmonary myeloid landscape.

ORGANISM(S): Mus musculus

PROVIDER: GSE295575 | GEO | 2025/08/04

REPOSITORIES: GEO

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