NFIL3/E4BP4 is a key transcription factor for CD8α⁺ dendritic cell development

Antigen presentation by mature dendritic cells (DCs) is the first step for initiating adaptive immune responses. DCs are composed of heterogeneous functional subsets; however, the molecular mechanisms that regulate differentiation of specific DC subsets are not understood. Here, we report that the basic leucine zipper transcription factor NFIL3/E4BP4 is essential for the development of CD8α⁺ conventional DCs (cDCs). Nfil3 ^-/- mice specifically lack CD8α⁺ cDCs but not CD8α⁺ cDCs or plasmacytoid DCs in lymphoid tissues. Flt3 ligand-dependent generation of CD8α⁺ cDCs in lymphoid tissues and CD8α⁺-equivalent cDCs from Nfil3^-/- bone marrow cells was also impaired. NFIL3 regulates CD8α⁺ cDC development in part through Batf3 expression. Importantly, Nfil3^-/- mice exhibited impaired cross-priming of CD8⁺ T cells against cellassociated antigen, a process normally performed by CD8α⁺ cDCs, and failed to produce IL-12 after TLR3 stimulation. Thus, NFIL3 plays an essential role in the development of CD8α⁺ cDCs.