USP18-Based Negative Feedback Control Is Induced by Type I and Type III Interferons and Specifically Inactivates Interferon a Response Ve´ ronique Franc¸ ois-Newton 1 , Gabriel Magno de Freitas Almeida2¤, Be´ atrice Payelle-Brogard1, Danie` le Monneron2, Lydiane Pichard-Garcia3, Jacob Piehler4, Sandra Pellegrini1., Gilles Uze´ 2*. 1 Institut Pasteur, Cytokine Signaling Unit, Centre National de la Recherche Scientifique, Unite´ de Recherche Associe´e 1961, Paris, France, 2 Centre National de la Recherche Scientifique, Unite´ Mixte de Recherche 5235, University of Montpellier II, Montpellier, France, 3 Institut National de la Sante´ Et de la Recherche Me´dicale, Unite´ 1040, Universite´ Montpellier I, Institut de Recherche en Biothe´rapie, Hoˆ pital Saint Eloi, Montpellier, France, 4 Division of Biophysics, University of Osnabru¨ ck, Osnabru¨ ck, Germany Abstract Type I interferons (IFN) are cytokines that are rapidly secreted upon microbial infections and regulate all aspects of the immune response. In humans 15 type I IFN subtypes exist, of which IFN a2 and IFN b are used in the clinic for treatment of different pathologies. IFN a2 and IFN b are non redundant in their expression and in their potency to exert specific bioactivities. The more recently identified type III IFNs (3 IFN l or IL-28/IL-29) bind an unrelated cell-type restricted receptor. Downstream of these two receptor complexes is a shared Jak/Stat pathway. Several mechanisms that contribute to the shut down of the IFN-induced signaling have been described at the molecular level. In particular, it has long been known that type I IFN induces the establishment of a desensitized state. In this work we asked how the IFN-induced desensitization integrates into the network built by the multiple type I IFN subtypes and type III IFNs. We show that priming of cells with either type I IFN or type III IFN interferes with the cell’s ability to further respond to all IFN a subtypes. Importantly, primed cells are differentially desensitized in that they retain sensitivity to IFN b. We show that USP18 is necessary and sufficient to induce differential desensitization, by impairing the formation of functional binding sites for IFN a2. Our data highlight a new type of differential between IFNs a and IFN b and underline a cross-talk between type I and type III IFN. This cross-talk could shed light on the reported genetic variation in the IFN l loci, which has been associated with persistence of hepatitis C virus and patient’s response to IFN a2 therapy. Citation: Franc¸ois-Newton V, Magno de Freitas Almeida G, Payelle-Brogard B, Monneron D, Pichard-Garcia L, et al. (2011) USP18-Based Negative Feedback Control Is Induced by Type I and Type III Interferons and Specifically Inactivates Interferon a Response. PLoS ONE 6(7): e22200. doi:10.1371/journal.pone.0022200 Editor: Karen L. Mossman, McMaster University, Canada Received March 4, 2011; Accepted June 16, 2011; Published July 14, 2011 Copyright: 2011 Franc¸ois-Newton et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007–2010) under grant agreement nu 223608 (SP, GU and JP). Also supported by grants from Institut Pasteur, Association pour la Recherche sur le Cancer (grant 3158 to SP and GU) and Centre National pour la Recherche Scientifique. VFN was supported by the Ministe`re de l’ Education Nationale, de la Recherche et de la Technologie. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: uze@univ-montp2.fr . These authors contributed equally to this work. ¤ Current address: Laborato´ rio de V´ırus, Instituto de Cieˆncias Biol o´gicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil Introduction Type I and type III (IL-28/29) IFNs form two multigenic families of pathogen-induced cytokines that exhibit common bioactivities through binding to unrelated cell surface receptors [1]. The numerous type I IFN subtypes (a/b/v) bind to a receptor made of the ubiquitously expressed IFNAR1 and IFNAR2 chains. Conversely, the type III IFNs (l1, 2, 3) bind to a receptor made of the broadly expressed IL-10R2 and of IFNLR1 (IL-28Ra) whose expression is cell type specific. Therefore, the response to type III IFNs is tissue specific and appears to be mainly restricted to epithelial cells [2]. Downstream of these two receptor complexes is a shared Jak/ Stat pathway, involving the Janus kinases Jak1 and Tyk2 that phosphorylate Stat1, Stat2 and Stat3. Activated Stat1/2 associate to IRF9 to yield the ISGF3 complex that induces transcription of IFN-stimulated genes (ISG) [1]. Thus, in humans, the 18 subtypes (13 a, 1 b, 1 v and 3 l) of the type I and type III IFN systems induce a same gene subset and exhibit antiviral and antiprolifer- ative activities through two independent cell surface receptors. In addition, the type I IFNs are recognized as mediators linking innate and adaptive immunity via their effect on the differentiation and maturation of dendritic cells and T cells, activities not shared with type III IFNs [3]. Among the type I IFNs, the a/v subtypes on the one hand and the b subtype on the other are not equivalent, as they are differentially produced upon microbial infections and exhibit distinct bioactivities. The biological potency of any given subtype is determined by both receptor binding parameters and receptor density on target cells [4,5]. Hence, compared to IFN a2, IFN b binds the receptor with higher affinity, forms a longer-lived complex and is more potent at inducing translational control signals, inhibiting cell growth and osteoclastogenesis [6,7,8] (Moraga et al., submitted). Importantly, IFN a2 is routinely used PLoS ONE | www.plosone.org 1 July 2011 | Volume 6 | Issue 7 | e22200