Zinc finger transcription factor zDC is a negative regulator required to prevent activation of classical dendritic cells in the steady state

Matthew M. Meredith, Kang Liu, Alice O. Kamphorst, Juliana Idoyaga, Arito Yamane, Pierre Guermonprez, Suzannah Rihn, K. H. Yao Kai-Hui, Israel T. Silva, Thiago Y. Oliveira, Dimitris Skokos, Rafael Casellas, Michel C. Nussenzweig

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1583-1593
Number of pages11
JournalJournal of Experimental Medicine
Volume209
Issue number9
DOIs
StatePublished - Aug 2012

Bibliographical note

Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.

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