p38α acts as a molecular switch to differentially regulate the Flt3 and CD115 pathways in dendritic cell development

DC development requires balanced signaling from cytokines, such as Fms-like tyrosine kinase 3 ligand (Flt3L) and macrophage colony-stimulating factor (M-CSF), but how these pathways are integrated to control lineage fate is not fully understood. Using a murine genetic model, we identified the kinase p38α as a central node that orchestrates this balance. We demonstrated that p38α, which acts as a critical effector downstream of Flt3L, is indispensable for plasmacytoid DC (pDC) differentiation. Mechanistically, the Flt3L-p38α pathway sustains the expression of the E3 ubiquitin ligase Nedd4, which mediates the degradation of the M-CSF receptor (CD115). Consequently, genetic deletion of p38α disrupts this primary Flt3L signaling cascade, leading to Nedd4 downregulation and triggering compensatory upregulation of surface CD115 expression on hematopoietic progenitors. This paradoxically enhanced their differentiation potential, leading to a numerical compensation of pDCs and increased overall myeloid repopulation; the resulting DCs were functionally impaired and exhibited defective production of type I/III interferons and IL-12. Crucially, this functional collapse abrogated their ability to orchestrate antitumor immunity. As a direct consequence, mice with p38α-deficient hematopoiesis failed to mount effective IFN-γ⁺CD8⁺ T-cell responses and were unable to control tumor growth. Our study reveals a novel p38α-Nedd4 molecular switch that integrates signaling from Flt3L and M-CSF to balance the quantity and functional quality of DCs, highlighting p38α as a key determinant of effective cancer immunosurveillance in a murine system.