title: Zinc finger transcription factor zDC is a negative regulator required to prevent activation of classical dendritic cells in the steady state.
abstract: Classical dendritic cells (cDCs) process and present antigens to T cells. Under steady-state conditions, antigen presentation by cDCs induces tolerance. In contrast, during infection or inflammation, cDCs become activated, express higher levels of cell surface MHC molecules, and induce strong adaptive immune responses. We recently identified a cDC-restricted zinc finger transcription factor, zDC (also known as Zbtb46 or Btbd4), that is not expressed by other immune cell populations, including plasmacytoid DCs, monocytes, or macrophages. We define the zDC consensus DNA binding motif and the genes regulated by zDC using chromatin immunoprecipitation and deep sequencing. By deleting zDC from the mouse genome, we show that zDC is primarily a negative regulator of cDC gene expression. zDC deficiency alters the cDC subset composition in the spleen in favor of CD8(+) DCs, up-regulates activation pathways in steady-state cDCs, including elevated MHC II expression, and enhances cDC production of vascular endothelial growth factor leading to increased vascularization of skin-draining lymph nodes. Consistent with these observations, zDC protein expression is rapidly down-regulated after TLR stimulation. Thus, zDC is a TLR-responsive, cDC-specific transcriptional repressor that is in part responsible for preventing cDC maturation in the steady state.
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Meredith
authors.forename: Kang
authors.initials: K
authors.lastname: Liu
authors.forename: Alice O
authors.initials: AO
authors.lastname: Kamphorst
authors.forename: Juliana
authors.initials: J
authors.lastname: Idoyaga
authors.forename: Arito
authors.initials: A
authors.lastname: Yamane
authors.forename: Pierre
authors.initials: P
authors.lastname: Guermonprez
authors.forename: Suzannah
authors.initials: S
authors.lastname: Rihn
authors.forename: Kai-Hui
authors.initials: KH
authors.lastname: Yao
authors.forename: Israel T
authors.initials: IT
authors.lastname: Silva
authors.forename: Thiago Y
authors.initials: TY
authors.lastname: Oliveira
authors.forename: Dimitris
authors.initials: D
authors.lastname: Skokos
authors.forename: Rafael
authors.initials: R
authors.lastname: Casellas
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D003713:Dendritic Cells / Q000276:immunology / Q000502:physiology*; D005786:Gene Expression Regulation; D042583:Lymphangiogenesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D051193:Toll-Like Receptors / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
chemical_list: D051193:Toll-Like Receptors; D014157:Transcription Factors; C574226:Zbtb46 protein, mouse