Using knockout- mice and retroviral delivery, Kim et al. showed that Irf8 is sufficient for DC progenitor development, and that Irf4 and Irf8 are redundant for cDC2 progenitor formation, but Irf4 is required to produce all cDC2 subsets. The shared cDC1/cDC2 transcriptional program used enhancers dependent on Ets-IRF composite elements operating at low IRF4 or IRF8 concentrations. cDC1-specific genes used AP1-IRF composite elements relying on high IRF4 or IRF8 concentrations and BATF3-dependent Irf8 autoactivation. A minority of cDC1-specific genes favored the IRF8 DNA binding domain.
Contributed by Paula Hochman
ABSTRACT: Development and function of conventional dendritic cell (cDC) subsets, cDC1 and cDC2, depend on transcription factors (TFs) IRF8 and IRF4, respectively. Since IRF8 and IRF4 can each interact with TF BATF3 at AP1-IRF composite elements (AICEs) and with TF PU.1 at Ets-IRF composite elements (EICEs), it is unclear how these factors exert divergent actions. Here, we determined the basis for distinct effects of IRF8 and IRF4 in cDC development. Genes expressed commonly by cDC1 and cDC2 used EICE-dependent enhancers that were redundantly activated by low amounts of either IRF4 or IRF8. By contrast, cDC1-specific genes relied on AICE-dependent enhancers, which required high IRF concentrations, but were activated by either IRF4 or IRF8. IRF8 was specifically required only by a minority of cDC1-specific genes, such as Xcr1, which could distinguish between IRF8 and IRF4 DNA-binding domains. Thus, these results explain how BATF3-dependent Irf8 autoactivation underlies emergence of the cDC1-specific transcriptional program.
Author Info: (1) Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA (2) Department of Oncology, Amgen Inc., 1120 Veterans B
Author Info: (1) Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA (2) Department of Oncology, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA (3) Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan (4) Howard Hughes Medical Institute, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA (5) Lead Contact
