Transcriptional profiling of wild-type (WT) and Ifnar1-SA (SA) in vitro differentiated Treg cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE182029 | GEO | 2021/08/15
REPOSITORIES: GEO
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Project description:Transcriptional profiling of wild-type (WT) and Ifnar1-SA (SA) in vitro differentiated Treg cells
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Project description:Tumor derived factors induced type I interferon receptor (IFNAR1) downregulation both in vivo and in vitro. IFNAR1 was shown to be phosphorylated, ubiquitinated and downregulated in response to soluble or vesicular tumor derived factors in a p38-dependent manner. Upon administration of B16F10 tumor derived factors, lungs of Ifnar1S526A knock-in mice (termed "SA"), where mutation in a phospho-acceptor site within the IFNAR1 phospho-degron renders IFNAR1 insensitive to p38-driven phosphorylation, ubiquitination and degradation, retained IFNAR1 and sustained the expression of the IFN stimulated genes. Futuremore, careful examination and validation of gene expression profiles revealed an increased expression of several chemokines known to attract neutrophils (including Cxcl1, Cxcl3 and Cxcl5) in the lungs of WT mice treated with tumor derived factors. This increase was notably less pronounced in the SA mice, suggesting that IFNAR1 downregulation by tumor derived factors induced neutrophil-attracting chemokines production.
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Project description:Single cell analysis of tumor infiltrating immune cells in wild-type (WT) and Ifnar1-SA (SA) mice
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Project description:Type I interferons (IFNs) are a family of cytokines that play an important role in regulating immune responses to pathogens and tumors and are used therapeutically. All IFNs are considered to signal via the heterodimeric IFNAR1-IFNAR2 complex, yet some subtypes such as IFN? can exhibit distinct functional properties, although the molecular basis of this is unclear. Here we demonstrate IFN uniquely and specifically ligates to IFNAR1 in an IFNAR2-independent manner and provide the structural basis of the IFNAR1-IFN interaction. We show that the IFNAR1-IFN complex transduces signals to modulate the expression of a set of genes independently of IFNAR2. Moreover, we show the in vivo importance of the IFNAR1-IFN signaling axis in a murine model of LPS-induced septic shock. Thus, we provide a molecular basis for understanding specific functions of IFN?. Interferon b induced gene expression in peritoneal exudate cells was measured 3hr post intra-peritoneal injection of 10,000IU/ml of interferon beta or saline into wildtype and Ifnar2-/- mice. Three independant experiments were performed for each treatment in both genotypes using different mice for each sample.
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Project description:Type I interferon (IFN-I) signals through two receptor subunits, IFNAR1 and IFNAR2, to regulate sterile and infectious immunity. IFNAR1 expression is tightly regulated to prevent autoimmunity although the mechanisms governing this are incompletely understood. We investigated the strategies used by two flaviviruses, tick-borne encephalitis virus and West Nile virus, to antagonize IFN-I signaling. Infection with these viruses resulted in depletion of IFNAR1 associated with the function of the viral IFN-I antagonist, NS5. NS5 function was dependent on its ability to associate with prolidase (PEPD), a cellular dipeptidase. PEPD was required for IFNAR1 maturation and accumulation, as well as gene induction following IFNAR1 stimulation. The relevance of PEPD to human biology was confirmed in fibroblasts derived from patients with genetic prolidase deficiency that expressed low IFNAR1 and exhibited reduced responses to IFNAR1. Thus, by understanding flavivirus IFN-I antagonism, PEPD is revealed as a central regulator of IFN-I responses in humans.
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