Dendritic cells (DCs) are a collection of different subtypes, each of which is characterized by specific surface markers, gene-expression patterns, and distinct functions. Members of the IFN regulatory factor family play critical roles in DC development and functions. Recently, Irf8 was shown to activate TGF-? signaling, which led to exacerbated neuroinflammation in the experimental autoimmune encephalomyelitis mouse model. We analyzed the effect of Irf8 on TGF-?/bone morphogenetic protein pathway-specific genes in DCs and identified Acvrl1, a type I TGF-? superfamily receptor, as a gene strongly induced by Irf8 expression. Among various DC subtypes, Acvrl1 is differentially expressed in CD8?(+) DCs. ACVRL1 signaling augmented Irf8-directed classical CD8?(+) DC development. Irf8 expression is essential for plasmacytoid DC and CD8?(+) DC development, and this study demonstrates that ACVRL1 signaling plays a pivotal role whereby it suppresses plasmacytoid DC development while enhancing that of CD8?(+) DCs, thus contributing to DC diversity development.
View details for DOI 10.4049/jimmunol.1501849
View details for Web of Science ID 000384999100004
View details for PubMedID 27421479
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?(+) DC-like cells, with a concomitant increase in plasmacytoid DC- and CD8?(+) 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?(+) DCs. We show that, without Irf8, expression of Id2 and Batf3 was not sufficient for directing classical CD8?(+) DC development. When coexpressed with Irf8, Batf3 and Id2 had a synergistic effect on classical CD8?(+) DC development. We demonstrate that Irf8 is upstream of Batf3 and Id2 in the classical CD8?(+) DC developmental program and define the hierarchical relationship of transcription factors important for classical CD8?(+) DC development.
View details for DOI 10.4049/jimmunol.1203541
View details for Web of Science ID 000328483900026
View details for PubMedID 24227775
View details for PubMedCentralID PMC4805111
Department Intranet