Induction of the transcription factor Irf8 in the common dendritic cell progenitor (CDP) is required for classical type 1 dendritic cell (cDC1) fate specification, but the mechanisms controlling this induction are unclear. Here we identified Irf8 enhancers via chromatin profiling of DCs and used CRISPR/Cas9 genome editing to assess their roles in Irf8 regulation. An enhancer 32 kilobases downstream of the Irf8 transcriptional start site (+32 kb Irf8 ) that was active in mature cDC1s was required for the development of this lineage, but not for its specification. Instead, a +41 kb Irf8 enhancer previously thought to be active only in plasmacytoid DCs was found to also be transiently accessible in cDC1 progenitors, and deleting this enhancer prevented the induction of Irf8 in CDPs and abolished cDC1 specification. Thus, cryptic activation of the +41 kb Irf8 enhancer in DC progenitors is responsible for cDC1 fate specification.

Highlights d cDC identity relies on cis-regulatory elements redundantly controlled by IRF4 and IRF8 d cDC1 is distinguished from cDC2 by the use of an AICEdependent gene program d An AICE-dependent gene program requires high levels of either IRF4 or IRF8 d Specific cis-regulatory elements distinguish between IRF4 and IRF8 DNA-binding domains

Innate immunity and adaptive immunity consist of highly specialized immune lineages that depend on transcription factors for both function and development. In this review, we dissect the similarities between two innate lineages, innate lymphoid cells (ILCs) and dendritic cells (DCs), and an adaptive immune lineage, T cells. ILCs, DCs, and T cells make up four functional immune modules and interact in concert to produce a specified immune response. These three immune lineages also share transcriptional networks governing the development of each lineage, and we discuss the similarities between ILCs and DCs in this review.

In the originally published article, the authors used chromatin immunoprecipitation sequencing (ChIP-seq) data for IRF4 to identify IRF4 binding sites in cDC2 for comparison with IRF8 binding sites in cDC1. However, due to an oversight during manuscript preparation, they did not upload the IRF4 ChIP-seq data to the GEO repository. This data has now been uploaded and available in data set GSE174011. The authors apologize for any inconvenience.