Batf3 maintains Irf8 autoactivation for commitment of a CD8α(+) cDC clonogenic progenitor

The transcription factors Batf3 and IRF8 are required for development of CD8α(+) conventional dendritic cells (cDCs), but the basis for their actions was unclear. Here, we identify two novel Zbtb46(+) progenitors that separately generate CD8α(+) and CD4(+) cDCs and arise directly from the common DC progenitor (CDP). Irf8 expression in the CDP depends on prior PU.1-dependent autoactivation, and specification of pre-CD8 DC progenitors requires IRF8 but not Batf3. However, upon pre-CD8 DC specification, Irf8 autoactivation becomes Batf3-dependent at a CD8α(+) cDC-specific enhancer containing multiple AP1-IRF composite elements (AICEs) within the Irf8 superenhancer. CDPs from Batf3(−/−) mice that specify toward pre-CD8 DCs fail to complete CD8α(+) cDC development due to decay of Irf8 autoactivation, and divert to the CD4(+) cDC lineage.