J Immunol. 2026 Nov 2;215(11):vkag305. doi: 10.1093/jimmun/vkag305.
ABSTRACT
Interferon regulatory factor 8 (IRF8) is a central transcription factor that governs the developmental program of type 1 classical dendritic cells (cDC1s). During cDC1 development, IRF8 expression continuously increases, reaching the high levels required for terminal differentiation and maintenance of cDC1 identity. Although the substantial contributions of IRF8 in cDC1 development have long been recognized, how bone marrow progenitors achieve and sustain high IRF8 levels remains an important question in the field. Recent studies have shown that a super-enhancer comprising multiple constituent enhancer elements controls Irf8 expression and is sequentially activated throughout cDC1 development. The Irf8 +56 kb enhancer, which is regulated by CCAAT/enhancer-binding protein (C/EBP) binding, initiates Irf8 expression in lymphoid-myeloid primed progenitors and establishes the earliest transcriptional priming toward the cDC1 lineage. The Irf8 +41 kb enhancer amplifies Irf8 expression during progenitor development from macrophage dendritic cell progenitors to pre-cDC1 progenitors. Finally, the Irf8 +32 kb enhancer becomes active after pre-cDC1 specification, enabling pre-cDC1 progenitors to sustain high IRF8 levels through BATF3-dependent autoactivation and complete cDC1 terminal differentiation. These enhancers regulate IRF8 at distinct cDC1 developmental stages via cooperative cis interactions and drive incremental increases in IRF8, with activation of each downstream enhancer depending on prior activation of the preceding enhancer.
PMID:43024830 | DOI:10.1093/jimmun/vkag305