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.

传统树突状细胞 (cDC) 亚群 cDC1 和 cDC2 的发育和功能分别取决于转录因子 (TF) IRF8 和 IRF4。由于 IRF8 和 IRF4 各自可以与 AP1-IRF 复合元件 (AICE) 上的 TF BATF3 相互作用，并与 Ets-IRF 复合元件 (EICE) 上的 TF PU.1 相互作用，因此尚不清楚这些因子如何发挥不同的作用。在这里，我们确定了 IRF8 和 IRF4 在 cDC 发育中不同作用的基础。 cDC1 和 cDC2 共同表达的基因使用 EICE 依赖性增强子，这些增强子被少量 IRF4 或 IRF8 冗余激活。相比之下，cDC1 特异性基因依赖于 AICE 依赖性增强子，这需要高 IRF 浓度，但会被 IRF4 或 IRF8 激活。只有少数 cDC1 特异性基因（例如Xcr1）特别需要 IRF8，该基因可以区分 IRF8 和 IRF4 DNA 结合域。因此，这些结果解释了 BATF3 依赖性Irf8自激活如何成为 cDC1 特异性转录程序出现的基础。