Conditional Stat1 ablation reveals the importance of interferon signaling for immunity to Listeria monocytogenes infection.
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.
Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
Elisabeth
E
Kernbauer
Verena
V
Maier
Dagmar
D
Stoiber
Birgit
B
Strobl
Christine
C
Schneckenleithner
Veronika
V
Sexl
Ursula
U
Reichart
Boris
B
Reizis
Ulrich
U
Kalinke
Amanda
A
Jamieson
Mathias
M
Müller
Thomas
T
Decker
D019264:Adoptive Transfer; D000818:Animals; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D005434:Flow Cytometry; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D007156:Immunologic Memory / Q000235:genetics / Q000276:immunology; D007370:Interferon Type I / Q000276:immunology*; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology
D007370:Interferon Type I; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse