Transcriptional Reprogramming of CD11b⁺Esam^hi Dendritic Cell Identity and Function by Loss of Runx3

Classical dendritic cells (cDC) are specialized antigen-presenting cells mediating immunity and tolerance. cDC cell-lineage decisions are largely controlled by transcriptional factor regulatory cascades. Using an in vivo cell-specific targeting of Runx3 at various stages of DC lineage development we show that Runx3 is required for cell-identity, homeostasis and function of splenic Esam^hi DC. Ablation of Runx3 in DC progenitors led to a substantial decrease in splenic CD4⁺/CD11b⁺ DC. Combined chromatin immunoprecipitation sequencing and gene expression analysis of purified DC-subsets revealed that Runx3 is a key gene expression regulator that facilitates specification and homeostasis of CD11b⁺Esam^hi DC. Mechanistically, loss of Runx3 alters Esam^hi DC gene expression to a signature characteristic of WT Esam^low DC. This transcriptional reprogramming caused a cellular change that diminished phagocytosis and hampered Runx3^-/- Esam^hi DC capacity to prime CD4⁺ T cells, attesting to the significant role of Runx3 in specifying Esam^hi DC identity and function.