Transcription factor E2-2 is an essential and specific regulator of plasmacytoid dendritic cell development.
Plasmacytoid dendritic cells (PDCs) represent a unique immune cell type specialized in type I interferon (IFN) secretion in response to viral nucleic acids. The molecular control of PDC lineage specification has been poorly understood. We report that basic helix-loop-helix transcription factor (E protein) E2-2/Tcf4 is preferentially expressed in murine and human PDCs. Constitutive or inducible deletion of murine E2-2 blocked the development of PDCs but not of other lineages and abolished IFN response to unmethylated DNA. Moreover, E2-2 haploinsufficiency in mice and in human Pitt-Hopkins syndrome patients was associated with aberrant expression profile and impaired IFN response of the PDC. E2-2 directly activated multiple PDC-enriched genes, including transcription factors involved in PDC development (SpiB, Irf8) and function (Irf7). These results identify E2-2 as a specific transcriptional regulator of the PDC lineage in mice and humans and reveal a key function of E proteins in the innate immune system.
Department of Microbiology, Columbia University Medical Center, New York, NY 10032, USA.
Babacar
B
Cisse
Michele L
ML
Caton
Manfred
M
Lehner
Takahiro
T
Maeda
Stefanie
S
Scheu
Richard
R
Locksley
Dan
D
Holmberg
Christiane
C
Zweier
Nicolette S
NS
den Hollander
Sarina G
SG
Kant
Wolfgang
W
Holter
Anita
A
Rauch
Yuan
Y
Zhuang
Boris
B
Reizis
D000293:Adolescent; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D006985:Hyperventilation / Q000276:immunology; D007113:Immunity, Innate; D008607:Intellectual Disability / Q000276:immunology; D007372:Interferons / Q000276:immunology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000276:immunology*; D013577:Syndrome; D051820:TCF Transcription Factors / Q000276:immunology*; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D051820:TCF Transcription Factors; C532096:TCF4 protein, human; C544894:TCF7L2 protein, human; C090743:Tcf4 protein, mouse; C544895:Tcf7l2 protein, mouse; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D007372:Interferons