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Conditional Stat1 ablation reveals the importance of interferon signaling for immunity to Listeria monocytogenes infection.

Kernbauer E, Maier V, Stoiber D, Strobl B, Schneckenleithner C, Sexl V, Reichart U, Reizis B, Kalinke U, Jamieson A, Müller M, Decker T - PLoS Pathog. (2012)

Bottom Line: T lymphocyte Stat1 reduced survival.Surprisingly, the effect of Stat1 signaling was much more pronounced, indicating a contribution of Stat1 to pathways other than the IFN-I pathway.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.

View Article: PubMed Central - PubMed

Affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.

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.

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Related in: MedlinePlus

Dendritic cell Stat1 regulates adaptive immunity.Splenocytes of immunised and rechallenged Stat1flfl and CD11cCreStat1flfl mice were isolated and evaluated for proliferating CD3+ cells (8A) and Tregs (CD3+, CD4+, FoxP3+, Ki67+) (8B). Means and standard deviations of one representative experiment out of two independently performed experiments are shown with 5 mice per group.
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ppat-1002763-g008: Dendritic cell Stat1 regulates adaptive immunity.Splenocytes of immunised and rechallenged Stat1flfl and CD11cCreStat1flfl mice were isolated and evaluated for proliferating CD3+ cells (8A) and Tregs (CD3+, CD4+, FoxP3+, Ki67+) (8B). Means and standard deviations of one representative experiment out of two independently performed experiments are shown with 5 mice per group.

Mentions: To further analyse the immunisation defects in CD11cCreStat1flfl mice, we investigated T cell responses after immunisation. Proliferation of splenic CD3+ T cells showed no significant differences (figure 8A). However, examination of the Treg population (CD4+Foxp3+) revealed an enhanced proliferative response in the spleens of mice with CD11c+-restricted Stat1 ablation (figure 8B). As regulatory T cells represent only a minor percentage of total splenic T cells it is not surprising that the difference in proliferation went unnoticed when analyzed in the context of total CD3+ T cell cells. The data suggest a contribution of DC Stat1 to the control of proliferation of a small proportion of antigen-specific Treg.


Conditional Stat1 ablation reveals the importance of interferon signaling for immunity to Listeria monocytogenes infection.

Kernbauer E, Maier V, Stoiber D, Strobl B, Schneckenleithner C, Sexl V, Reichart U, Reizis B, Kalinke U, Jamieson A, Müller M, Decker T - PLoS Pathog. (2012)

Dendritic cell Stat1 regulates adaptive immunity.Splenocytes of immunised and rechallenged Stat1flfl and CD11cCreStat1flfl mice were isolated and evaluated for proliferating CD3+ cells (8A) and Tregs (CD3+, CD4+, FoxP3+, Ki67+) (8B). Means and standard deviations of one representative experiment out of two independently performed experiments are shown with 5 mice per group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3375314&req=5

ppat-1002763-g008: Dendritic cell Stat1 regulates adaptive immunity.Splenocytes of immunised and rechallenged Stat1flfl and CD11cCreStat1flfl mice were isolated and evaluated for proliferating CD3+ cells (8A) and Tregs (CD3+, CD4+, FoxP3+, Ki67+) (8B). Means and standard deviations of one representative experiment out of two independently performed experiments are shown with 5 mice per group.
Mentions: To further analyse the immunisation defects in CD11cCreStat1flfl mice, we investigated T cell responses after immunisation. Proliferation of splenic CD3+ T cells showed no significant differences (figure 8A). However, examination of the Treg population (CD4+Foxp3+) revealed an enhanced proliferative response in the spleens of mice with CD11c+-restricted Stat1 ablation (figure 8B). As regulatory T cells represent only a minor percentage of total splenic T cells it is not surprising that the difference in proliferation went unnoticed when analyzed in the context of total CD3+ T cell cells. The data suggest a contribution of DC Stat1 to the control of proliferation of a small proportion of antigen-specific Treg.

Bottom Line: T lymphocyte Stat1 reduced survival.Surprisingly, the effect of Stat1 signaling was much more pronounced, indicating a contribution of Stat1 to pathways other than the IFN-I pathway.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.

View Article: PubMed Central - PubMed

Affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.

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.

Show MeSH
Related in: MedlinePlus