Although CD103-expressing dendritic cells (DCs) are widely present in nonlymphoid tissues, the transcription factors controlling their development and their relationship to other DC subsets remain unclear. Mice lacking the transcription factor Batf3 have a defect in the development of CD8α+ conventional DCs (cDCs) within lymphoid tissues. We demonstrate that Batf3−/− mice also lack CD103+CD11b− DCs in the lung, intestine, mesenteric lymph nodes (MLNs), dermis, and skin-draining lymph nodes. Notably, Batf3−/− mice displayed reduced priming of CD8 T cells after pulmonary Sendai virus infection, with increased pulmonary inflammation. In the MLNs and intestine, Batf3 deficiency resulted in the specific lack of CD103+CD11b− DCs, with the population of CD103+CD11b+ DCs remaining intact. Batf3−/− mice showed no evidence of spontaneous gastrointestinal inflammation and had a normal contact hypersensitivity (CHS) response, despite previous suggestions that CD103+ DCs were required for immune homeostasis in the gut and CHS. The relationship between CD8α+ cDCs and nonlymphoid CD103+ DCs implied by their shared dependence on Batf3 was further supported by similar patterns of gene expression and their shared developmental dependence on the transcription factor Irf8. These data provide evidence for a developmental relationship between lymphoid organ–resident CD8α+ cDCs and nonlymphoid CD103+ DCs.

The zinc finger transcription factor Zbtb46 specifically marks cDCs and their committed precursors and, when overexpressed in BM progenitors, promotes cDC development at the expense of granulocytes.

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.

The AP-1 transcription factor Batf3 is required for homeostatic development of CD8α+ classical dendritic cells that prime CD8 T-cell responses against intracellular pathogens. Here, we identify an alternative, Batf3-independent pathway for their development operating during infection with intracellular pathogens mediated by the cytokines IL-12 and IFN-γ. This alternative pathway results from molecular compensation for Batf3 provided by the related AP-1 factors Batf, which also functions in T and B cells, and Batf2 induced by cytokines in response to infection. Reciprocally, physiologic compensation between Batf and Batf3 also occurs in T cells for expression of IL-10 and CTLA-4. Compensation among BATF factors is based on the shared capacity of their leucine zipper domains to interact with non-AP-1 factors such as Irf4 and Irf8 to mediate cooperative gene activation. Conceivably, manipulating this alternative pathway of dendritic cell development could be of value in augmenting immune responses to vaccines.