Fig. 2: The basis for cDC1/cDC2 diversity lies in the activation of an AICE-dependent gene program.

In cDC1s, the Irf8 gene undergoes autoactivation through the action of an IRF8:BATF3 complex binding to an enhancer located +32 kb downstream of the Irf8 promoter. This autoactivation maintains high levels of IRF8 expression in the maturing cDC1 of a specific progenitor. In contrast, in cDC2s, the level of Irf8 is not maintained, and both IRF4 and IRF8 are expressed together but at much lower levels. This level of IRF4 and IRF8 expressed in cDC2s is sufficient to activate the EICE-dependent program that controls the expression of genes expressed in cDCs, both in cDC1s and cDC2s, such as Zbtb46. However, in cDC1s, the expression of IRF8 is much higher and sufficient to activate the program of genes that also require occupation of AICE cis-acting elements, such as the cDC1-specific gene Snx22. In Irf4 deficiency, a low level of IRF8 protein is sufficient to maintain the expression of some common cDC genes, but the induction of certain genes is inadequate for induction of some certain responses.