Abstract
Signal transducer and activator of transcription 1 (Stat1) is a key player in responses to interferons (IFN). Mutations of Stat1 cause severe immune deficiencies in humans and mice. Here we investigate the importance of Stat1 signaling for the innate and secondary immune response to the intracellular bacterial pathogen Listeria monocytogenes (Lm). Cell type-restricted ablation of the Stat1 gene in naïve animals revealed unique roles in three cell types: macrophage Stat1 signaling protected against lethal Lm infection, whereas Stat1 ablation in dendritic cells (DC) did not affect survival. T lymphocyte Stat1 reduced survival. Type I IFN (IFN-I) signaling in T lymphocytes reportedly weakens innate resistance to Lm. Surprisingly, the effect of Stat1 signaling was much more pronounced, indicating a contribution of Stat1 to pathways other than the IFN-I pathway. In stark contrast, Stat1 activity in both DC and T cells contributed positively to secondary immune responses against Lm in immunized animals, while macrophage Stat1 was dispensable. Our findings provide the first genetic evidence that Stat1 signaling in different cell types produces antagonistic effects on innate protection against Lm that are obscured in mice with complete Stat1 deficiency. They further demonstrate a drastic change in the cell type-dependent Stat1 requirement for memory responses to Lm infection.
Highlights
Signal transducer and activator of transcription (Stat1) is a central mediator of interferon responses in the immune system
STAT1 in the hematopoietic compartment is crucial for host protection to Listeria monocytogenes infection
This suggests that hepatocytes, representing an important niche for Listeria monocytogenes (Lm) multiplication [32,33], are not protected by Signal transducer and activator of transcription 1 (Stat1) signaling
Summary
Signal transducer and activator of transcription (Stat1) is a central mediator of interferon responses in the immune system. Signals from type I (IFNa/IFNb; IFN-I), type II (IFNc; IFN-II) and type III (IFNl, IFN-III) interferons employ receptor-associated Janus kinases (Jaks) to activate Stats by tyrosine phosphorylation [1,2]. The central character of Stat in signal transduction by the IFN receptors results from the importance of Stat homodimers for transcriptional regulation by IFNc. Stat forms the ISGF3 complex together with Stat and interferon regulatory factor 9 (Irf). Consistent with its central role, Stat deficiency in mice recapitulates the lack of IFN-I, IFN-III and IFNc responses and leads to high susceptibility to viral and bacterial infections [6,7,8]. Patients with various degrees of Stat loss-of-function present clinically with recurrent and often lethal mycobacterial and viral infections [9,10,11]
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