GM-CSF derived from alveolar type 2 cells promotes CD301b+ cDC2 generation and allergic airway inflammation

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 cell-intrinsic role for granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling in the development of a CD301b⁺ subset of terminally differentiated cDC2s, in addition to CD103⁺XCR1⁺ cDC1s. Unbiased single-cell transcriptomic profiling of CD11c⁺ cells identified both immature and differentiated lung cDC populations. GM-CSF deficiency disrupted antiapoptotic Bcl2a1 up-regulation and impaired progression to the CD301b⁺ transcriptional state. Despite the positioning of CD301b⁺ cDC2s in lymphoid cell-rich adventitial cuff areas, hematopoietic GM-CSF was dispensable for their development. Instead, alveolar epithelial type 2 cell-derived GM-CSF was 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.