Dendritic cells require STAT-1 phosphorylated at its transactivating domain for the induction of peptide-specific CTL

A Pilz, W Kratky, S Stockinger, O Simma… - The Journal of …, 2009 - journals.aai.org
A Pilz, W Kratky, S Stockinger, O Simma, U Kalinke, K Lingnau, A von Gabain, D Stoiber
The Journal of Immunology, 2009journals.aai.org
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 …
Abstract
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-γ-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.
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