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Dendritic Cells Require STAT-1 Phosphorylated at Its Transactivating Domain for the Induction of Peptide-Specific CTL¹

Andreas Pilz^*, Wolfgang Kratky^*, Silvia Stockinger^*, Olivia Simma^*,, Ulrich Kalinke^||,#, Karen Lingnau, Alexander von Gabain, Dagmar Stoiber, Veronika Sexl, Thomas Kolbe, Thomas Rülicke, Mathias Müller^¶ and Thomas Decker^2,*

^* Max F. Perutz Laboratories, Department of Genetics, Microbiology and Immunobiology, University of Vienna, Intercell AG, Campus Vienna Biocenter 3, Department of Pharmacology, Medical University of Vienna, and Biomodels Austria, ^¶ Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria; ^|| Paul-Ehrlich-Institut, Langen, Germany; and ^# Twincore-Centre for Experimental and Clinical Infection Research, Hannover, Germany

Phosphorylation of transcription factor STAT-1 on Y701 regulates subcellular localization whereas phosphorylation of the transactivating domain at S727 enhances transcriptional activity. In this study, we investigate the impact of STAT-1 and the importance of transactivating domain phosphorylation on the induction of peptide-specific CTL in presence of the TLR9-dependent immune adjuvant IC31. STAT-1 deficiency completely abolished CTL induction upon immunization, which was strongly reduced in animals carrying the mutation of the S727 phospho-acceptor site. A comparable reduction of CTL was found in mice lacking the type I IFN (IFN-I) receptor, whereas IFN--deficient mice behaved like wild-type controls. This finding suggests that S727-phosphorylated STAT-1 supports IFN-I-dependent induction of CTL. In adoptive transfer experiments, IFN-I- and S727-phosphorylated STAT-1 were critical for the activation and function of dendritic cells. Mice with a T cell-specific IFN-I receptor ablation did not show impaired CTL responses. Unlike the situation observed for CTL development S727-phosphorylated STAT-1 restrained proliferation of naive CD8⁺ T cells both in vitro and following transfer into Rag-deficient mice. In summary, our data reveal a dual role of S727-phosphorylated STAT-1 for dendritic cell maturation as a prerequisite for the induction of CTL activity and for T cell autonomous control of activation-induced or homeostatic proliferation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the project SFB 28 by the Austrian Science Foundation (FWF) (to T.D., V.S., and M.M.) and the Austrian Research Promotion Agency through the BRIDGE programme.

² Address correspondence and reprint requests to Dr. Thomas Decker, Max F. Perutz Laboratories, Department of Genetics, Microbiology and Immunobiology, University of Vienna, Dr. Bohr-Gasse 9/4, Vienna, Austria. E-mail address: Thomas.decker{at}univie.ac.at

³ Abbreviations used in this paper: IFN-I, type I IFN; IFNAR, IFN-I -chain receptor; ISGF, IFN-stimulated gene factor; DC, dendritic cell; BMDC, bone marrow-derived DC; MHC I, MHC class I; wt, wild type.