SoumelisJEM

SoumelisJEM - BRIEF DEFINITIVE REPORT PI3K is critical for...

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The Journal of Experimental Medicine JEM © The Rockefeller University Press $30.00 Vol. 205, No. 2, February 18, 2008 315-322 www.jem.org/cgi/doi/ 315 10.1084/jem.20070763 BRIEF DEFINITIVE REPORT Plasmacytoid pre-DCs (pDCs) are the main type I IFN producers in humans and mice ( 1 ). They play a key role in innate antiviral immune re- sponses but can also evolve into potent APCs and be important players in adaptive response ( 1, 2 ). Activation of pDCs through Toll-like receptor (TLR) 7 and 9 can trigger both types of response, including large quantities of type I IFN pro- duction and/or DC di± erentiation ( 1 ). Synthetic CpG-containing oligonucleotides of the types A and B (CpG-A and -B) selectively induce type I IFN production and DC di± erentiation, respec- tively ( 3 ), whereas some microbial stimuli such as influenza virus (Flu), HSV, or CpG-C can simultaneously induce both responses ( 1 ). Two factors seem to be key for the induction of large quantities of type I IFN in pDCs: (a) the ability of the TLR ligand to bind its receptor in the early endosomal compartments ( 4, 5 ) and (b) the phosphorylation and nuclear translocation of the transcription factor IFN regulatory factor (IRF) 7 ( 6 ). This last step was shown to depend on IL-1 receptor – associated kinase 1 ( 7 ) and I k B kinase (IKK) a ( 8 ) in mouse pDCs. However, the molecular switch regulating type I IFN pro- duction versus DC di± erentiation in pDCs is not fully elucidated and could have important clinical implications, considering the link be- tween a dysregulated TLR-induced IFN re- sponse and autoimmune diseases ( 9, 10 ). The phosphatidylinositol-3 kinase (PI3K) pathway is involved in a variety of biological processes, including cell survival and prolifera- tion, B and T cell receptor signaling, and activa- tion of G protein – coupled receptors, such as chemokine receptors ( 11 ). PI3K contains regu- latory subunits (p85 a and b ) and catalytic sub- units (p110 a , b , g , and d ). PI3K g and d are preferentially expressed in cells of hemopoietic CORRESPONDENCE Franck J. Barrat: ±fbarrat@dynavax.com±± ±OR±± Vassili Soumelis: ±vassili.soumelis@curie.net F.J. Barrat and V. Soumelis contributed equally to this work. The online version of this article contains supplemental material. PI3K is critical for the nuclear translocation of IRF-7 and type I IFN production by human plasmacytoid predendritic cells in response to TLR activation Cristiana Guiducci , 1 Cristina Ghirelli , 2,3 Marie-Annick Marloie-Provost , 2 Tracy Matray , 1 Robert L. Co± man , 1 Yong-Jun Liu , 4 Franck J. Barrat , 1 and Vassili Soumelis 2,3 1 Dynavax Technologies Corporation, Berkeley, CA 94710 2 Department of Immunology, Institut Curie, 75005 Paris, France 3 Institut National de la Sant é et de la Recherche M é dicale, U653, 75005 Paris, France 4 Department of Immunology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030 Plasmacytoid predendritic cells (pDCs) are the main producers of type I interferon (IFN) in response to Toll-like receptor (TLR) stimulation. Phosphatidylinositol-3 kinase (PI3K) has
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SoumelisJEM - BRIEF DEFINITIVE REPORT PI3K is critical for...

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