Batf3 and Id2 Have a Synergistic Effect on Irf8-Directed Classical CD8α+ Dendritic Cell Development

Dendritic cells (DCs) are heterogeneous cell populations represented by different subtypes, each varying in terms of gene expression patterns and specific functions. Recent studies identified transcription factors essential for the development of different DC subtypes, yet molecular mechanisms for the developmental program and functions remain poorly understood. In this study, we developed and characterized a mouse DC progenitor-like cell line, designated DC9, from Irf8(-/-) bone marrow cells as a model for DC development and function. Expression of Irf8 in DC9 cells led to plasmacytoid DCs and CD8 alpha(+) DC-like cells, with a concomitant increase in plasmacytoid DC-and CD8 alpha(+) DC-specific gene transcripts and induction of type I IFNs and IL12p40 following TLR ligand stimulation. Irf8 expression in DC9 cells led to an increase in Id2 and Batf3 transcript levels, transcription factors shown to be important for the development of CD8 alpha(+) DCs. We show that, without Irf8, expression of Id2 and Batf3 was not sufficient for directing classical CD8 alpha(+) DC development. When coexpressed with Irf8, Batf3 and Id2 had a synergistic effect on classical CD8 alpha(+) DC development. We demonstrate that Irf8 is upstream of Batf3 and Id2 in the classical CD8 alpha(+) DC developmental program and define the hierarchical relationship of transcription factors important for classical CD8 alpha(+) DC development.