Zeb2 is required for development of plasmacytoid dendritic cells

Abstract

Abstract Recent work has shown that the transcription factor Zeb2 is regulated by and cooperates with T-bet to promote terminal differentiation of NK cells and cytotoxic T cells. In the mouse, Zeb2 is expressed throughout dendritic cell (DC) development and in mature plasmacytoid DCs (pDCs) and CD11b+ classical DCs (cDCs), but not in CD8+/CD103+ cDCs. We hypothesized that downregulation of Zeb2 expression would be essential for the development of CD8+/CD103+ cDCs. Upon conditional deletion of Zeb2, we observed a substantial decrease in pDC frequency and an increased ratio of CD8+:CD11b+ cDCs; meanwhile, Zeb2 haploinsufficiency yielded a partial defect in pDC development. Additional experiments demonstrated that this defect was cell-intrinsic and durable, and that it could not be rescued by administration of type I interferon, which increased pDC frequency in cultures of wild-type DC progenitors but directed Zeb2-deficient DC progenitors almost entirely to the CD8+/CD103+ cDC lineage. Deletion of Zeb2 induced by poly(I:C) treatment in an Mx1-Cre-driven model also resulted in perturbations in other myeloid lineages. Although poly(I:C) treatment led to an acute loss of Ly-6Chi monocytes both in Zeb2fl/fl;Mx1-Cre(tg) mice and in control mice, those monocytes were replenished to baseline frequencies in control mice but not in Zeb2-deficient mice. Similar decreases in monocyte frequency were observed in other organs, and further experiments suggested that this defect was also cell-intrinsic, gene dosage-dependent, durable, and observable in model systems that do not require use of poly(I:C). Thus, we have identified an essential regulator of development in multiple myeloid lineages.