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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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Analysis of serum cytokines in mice with cell-type specific Stat1 ablation 72 hrs after infection with Lm.Mice with Stat1 ablation in different cell compartments were infected with 1×10∧5 Lm and serum was collected over the course of three days after infection. Indicated cytokines (MCP1, IL6, IFNγ, IL12p70, MCP3, Rantes, MIP1β, IL22) were analysed (4). Mean values of cumulative data out of two experiments (n = 8) are depicted with standard deviations. Significant differences are indicated using asterisks.
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ppat-1002763-g004: Analysis of serum cytokines in mice with cell-type specific Stat1 ablation 72 hrs after infection with Lm.Mice with Stat1 ablation in different cell compartments were infected with 1×10∧5 Lm and serum was collected over the course of three days after infection. Indicated cytokines (MCP1, IL6, IFNγ, IL12p70, MCP3, Rantes, MIP1β, IL22) were analysed (4). Mean values of cumulative data out of two experiments (n = 8) are depicted with standard deviations. Significant differences are indicated using asterisks.

Mentions: Examination of systemic cytokine/chemokine levels demonstrated that mice lacking myeloid Stat1 signaling show increased levels of IL6, IL12p70, MCP1, MCP3, IL22, MIP1β, Rantes and IFNγ in their serum, similar to but not as dramatic as complete Stat1 deficiency (figure 4). As these mice have strongly elevated numbers of pathogens in their organs the increase in inflammatory cytokines may again reflect an increased activity of the innate immune system. Alternatively, increased cytokine production could also result from the loss of Stat1-mediated gene repression as reported for IL6 [39]. The function of Stat1 as both a transcriptional activator and repressor is well documented [40]. Both functions require binding to GAS sequences [41], but the detailed mechanisms are not understood.


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)

Analysis of serum cytokines in mice with cell-type specific Stat1 ablation 72 hrs after infection with Lm.Mice with Stat1 ablation in different cell compartments were infected with 1×10∧5 Lm and serum was collected over the course of three days after infection. Indicated cytokines (MCP1, IL6, IFNγ, IL12p70, MCP3, Rantes, MIP1β, IL22) were analysed (4). Mean values of cumulative data out of two experiments (n = 8) are depicted with standard deviations. Significant differences are indicated using asterisks.
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1002763-g004: Analysis of serum cytokines in mice with cell-type specific Stat1 ablation 72 hrs after infection with Lm.Mice with Stat1 ablation in different cell compartments were infected with 1×10∧5 Lm and serum was collected over the course of three days after infection. Indicated cytokines (MCP1, IL6, IFNγ, IL12p70, MCP3, Rantes, MIP1β, IL22) were analysed (4). Mean values of cumulative data out of two experiments (n = 8) are depicted with standard deviations. Significant differences are indicated using asterisks.
Mentions: Examination of systemic cytokine/chemokine levels demonstrated that mice lacking myeloid Stat1 signaling show increased levels of IL6, IL12p70, MCP1, MCP3, IL22, MIP1β, Rantes and IFNγ in their serum, similar to but not as dramatic as complete Stat1 deficiency (figure 4). As these mice have strongly elevated numbers of pathogens in their organs the increase in inflammatory cytokines may again reflect an increased activity of the innate immune system. Alternatively, increased cytokine production could also result from the loss of Stat1-mediated gene repression as reported for IL6 [39]. The function of Stat1 as both a transcriptional activator and repressor is well documented [40]. Both functions require binding to GAS sequences [41], but the detailed mechanisms are not understood.

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