Comprehensive transcriptomic profiling uncovers an inflammatory maturation program conserved in human and mouse...

Conventional dendritic cells (cDCs) integrate signals to balance tolerance and immunity, but how steady-state cDC programs are changed during inflammatory maturation remains incompletely resolved. Here, using Seqtometry-based analysis of mouse and human cDCs, we identify distinct steady-state cDC1 gene programs enriched for either tolerance-associated or immune response-associated (pre-immunogenic) transcriptomic features that are present under homeostatic conditions in fully differentiated cDCs with divergent predicted immune functions. Under inflammatory conditions, the tolerance-linked features are reduced, whereas the pre-immunogenic program is extended in response to type I interferon signaling and is selectively impaired by Ifnar1 deficiency. This core inflammatory program is conserved across mouse and human cDC subsets, and while retaining disease-specific transcriptomic features, it is detected in infection, cancer, and autoimmunity. Together, these findings establish a gene program-based framework for cDC inflammatory maturation that extends beyond a binary immature-versus-mature classification and supports the identification of disease-associated cDC biomarkers.