title: Dendritic cell lineage commitment is instructed by distinct cytokine signals.
abstract: Dendritic cells (DC) develop from hematopoietic stem cells, which is guided by instructive signals through cytokines. DC development progresses from multipotent progenitors (MPP) via common DC progenitors (CDP) into DC. Flt3 ligand (Flt3L) signaling via the Flt3/Stat3 pathway is of pivotal importance for DC development under steady state conditions. Additional factors produced during steady state or inflammation, such as TGF-β1 or GM-CSF, also influence the differentiation potential of MPP and CDP. Here, we studied how gp130, GM-CSF and TGF-β1 signaling influence DC lineage commitment from MPP to CDP and further into DC. We observed that activation of gp130 signaling promotes expansion of MPP. Additionally, gp130 signaling inhibited Flt3L-driven DC differentiation, but had little effect on GM-CSF-driven DC development. The inflammatory cytokine GM-CSF induces differentiation of MPP into inflammatory DC and blocks steady state DC development. Global transcriptome analysis revealed a GM-CSF-driven gene expression repertoire that primes MPP for differentiation into inflammatory DC. Finally, TGF-β1 induces expression of DC-lineage affiliated genes in MPP, including Flt3, Irf-4 and Irf-8. Under inflammatory conditions, however, the effect of TGF-β1 is altered: Flt3 is not upregulated, indicating that an inflammatory environment inhibits steady state DC development. Altogether, our data indicate that distinct cytokine signals produced during steady state or inflammation have a different outcome on DC lineage commitment and differentiation.
authors.affiliation: Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Aachen, Germany. kristin.sere@rwth-aachen.de
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Seré
authors.forename: Qiong
authors.initials: Q
authors.lastname: Lin
authors.forename: Piritta
authors.initials: P
authors.lastname: Felker
authors.forename: Nina
authors.initials: N
authors.lastname: Rehage
authors.forename: Theresa
authors.initials: T
authors.lastname: Klisch
authors.forename: Inga
authors.initials: I
authors.lastname: Ortseifer
authors.forename: Thomas
authors.initials: T
authors.lastname: Hieronymus
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Martin
authors.initials: M
authors.lastname: Zenke
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology*; D015870:Gene Expression; D006410:Hematopoiesis / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D016207:Cytokines