Project description:Type 1 interferons (IFNs) induce complex responses that can be beneficial or deleterious, depending on context. Greater understanding of the mechanisms of action of these cytokines could allow new therapeutic approaches. We found that type 1 IFNs induced changes in cellular metabolism that were critical for changes in target cell function. This was apparent in plasmacytoid dendritic cells, which are specialized for type 1 IFN production, where toll-like receptor-9 (TLR9)-dependent activation was found to be dependent on increased fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) induced by autocrine signaling through the type 1 IFN receptor (IFNAR). Type 1 IFNs also induced FAO/OXPHOS in non-hematopoietic cells and were found to be responsible for increased FAO/OXPHOS in virus-infected cells. Increased FAO/OXPHOS in response to IFNAR signaling was regulated by the nuclear receptor PPARα. Our findings reveal PPARα/FAO/OXPHOS as potential targets to therapeutically modulate downstream effects of type 1 IFNs. mRNA profiles of overnight stimulated plasmacytoid dendritic cells, activated with CpG or INFa. Samples analyzed in triplicate, with HiSeq 2500 byâ/ 50bpX25bp pair-end sequencing
Project description:Type 1 interferons (IFNs) induce complex responses that can be beneficial or deleterious, depending on context. Greater understanding of the mechanisms of action of these cytokines could allow new therapeutic approaches. We found that type 1 IFNs induced changes in cellular metabolism that were critical for changes in target cell function. This was apparent in plasmacytoid dendritic cells, which are specialized for type 1 IFN production, where toll-like receptor-9 (TLR9)-dependent activation was found to be dependent on increased fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) induced by autocrine signaling through the type 1 IFN receptor (IFNAR). Type 1 IFNs also induced FAO/OXPHOS in non-hematopoietic cells and were found to be responsible for increased FAO/OXPHOS in virus-infected cells. Increased FAO/OXPHOS in response to IFNAR signaling was regulated by the nuclear receptor PPARα. Our findings reveal PPARα/FAO/OXPHOS as potential targets to therapeutically modulate downstream effects of type 1 IFNs.
Project description:Type I Interferons (IFN-I) stimulate pro-inflammatory programs critical for immune activation, but also induce immune-suppressive feedback circuits that contribute to the failure of cancer control. Yet, how IFN-Is differentially induce these opposing programs remains enigmatic. We establish that the transcription factor Interferon Regulatory Factor 2 (IRF2) is a central feedback molecule attenuating IFN signaling and driving CD8 T cell exhaustion in the tumor microenvironment. IRF2 inhibits CD8 T cell effector function in response to sustained interferon signaling by programming T cell exhaustion. Lineage-specific deletion of IRF2 limits CD8 T cells exhaustion to maintain effector functions, thereby enabling long-term tumor control, and increased responsiveness to immune-checkpoint and adoptive cell therapies. Long-term tumor control by IRF2-deficient CD8 T cells is dependent on continuous integration of both IFN-I and IFN? signals, which in the absence of IRF2, potentiate sustained effector function instead of exhaustion. Thus, IRF2 redirects IFN signalling to drive T cell exhaustion and prevent tumor control.
Project description:We have developed highly potent synthetic activators of the vertebrate immune system that specifically target the RIG-I receptor. When introduced into mice, a family of short, triphosphorylated Stem Loop RNAs (SLRs) induces a potent interferon response and the activation of specific genes essential for antiviral defense. Using RNAseq, we provide the first in-vivo genome-wide view of the expression networks that are initiated upon RIG-I activation. We observe that SLRs specifically induce type I interferons, subsets of interferon-stimulated genes (ISGs), and cellular remodeling factors. By contrast, poly(I:C), which binds and activates multiple RNA sensors, induces type III interferons and several unique ISGs. The short length (10-14 base pairs) and robust function of SLRs in mice demonstrate that RIG-I forms active signaling complexes without oligomerizing on RNA. These findings demonstrate that SLRs are potent therapeutic and investigative tools for targeted modulation of the innate immune system.
Project description:Interferon is effective at inducing complete remissions in patients with Chronic Myelogenous Leukemia (CML), and evidence supports an immune mechanism. Here we show that the Type I Interferons (alpha and beta) regulate expression of the Interferon consensus sequence binding protein (ICSBP) in bcr-abl transformed cells and as shown previously for ICSBP, induce a vaccine-like immunoprotective effect in a murine model of bcr-abl induced leukemia. We identify the chemokines CCL6 and CCL9 as genes prominently induced by the Type I Interferons and ICSBP, and demonstrate that these immunomodulators are required for the immunoprotective effect of ICSBP expression. Insights into the role of these chemokines in the anti-leukemic response of interferons suggest new strategies for immunotherapy of CML.
Project description:The defense mechanisms that are provided by the innate immune system are a formidable barrier to influenza virus and a special immune system exists at distinct respiratory epithelium to combat invasion by influenza virus. Innate immune mechanisms for antiviral resistance are mediated by an increase of interferons’ secretion and type I and III IFNs represent the prototypical resistance mechanism as they induce diverse of Interferon stimulated genes that serve as effectors to limit viral replication.
Project description:The class I major histocompatibility complex (MHC) bound peptides, produced from immature proteins that are degraded rapidly are called defective ribosome products (DRiPs). Such DRiPs are possibly involved with early alerting of the immune system about impeding infections, thus bringing about faster killing of infected cells before the viruses replicate. Interferons are a major group of cytokines, produced in response to viral infection. The interferons modulate the cellular metabolism and gene expression patterns and increase the expression and cell-surface presentation of the MHC molecules, helping this way coping with the viral infection. In this study, we evaluated whether the interferons also induce rapid degradation of cellular or viral proteins and produce DRiPs MHC-bound peptides to help the alert of the immune system. Cultured human breast cancer cells were treated with interferons and the cells were transferred to growth media containing heavy stable isotope labeled amino acids (dynamic-SILAC)in several time points a few hours after the interferons’ treatment. The rates of synthesis, degradation, and production of the cellular protein and their degradation products, the MHC peptides, were followed by LC-MS/MS analyses. Detection of large numbers of MHC peptides that incorporate the heavy amino acids into them, faster than their source proteins, indicated to us that not only DRiP-peptides are rather abundant among the MHC peptidome, but that the interferons increase significantly the presentation of DRiP-peptides. Importantly, much of this DRiPome derive from multi-subunit complexes, including the proteasomes and ribosomes, while the degradation of the standard protostome give rise to the immunoproteasome, which is thought to produce peptides that enhance the immune-response; the degradation of the ribosome subunits may aid in reducing the synthesis of viral infection
Project description:In addition to microbiota-host interaction on inflammatory response, many enzymes, including three enzymes critical in gluconeogenesis and transport of amino acids and carbohydrates in energy metabolism, are dependent on the Ca/Mg ratio, indicating critical roles of the Ca/Mg ratio in carbohydrate fermentation and energy metabolism in bacteria. In pilot metagenomic study conducted by the investigators, they found all the significantly changed biologic functions within the microbial community caused by a reduction in the Ca/Mg ratio are biologically dependent on the Ca/Mg ratio or Mg. It is striking that the functions with significant changes in stool samples were centered on the fermentation of carbohydrates and energy metabolism while the functions in rectal swabs were related to immune response. Tissue also had a distinct profile from stool and swab.
These findings have very broad clinical and public health significance for many inflammation-related diseases or metabolic disorders. Due to the small sample size in the pilot study, the investigators plan to confirm these findings using the biospecimens collected in the parent study (Personalized Prevention of Colorectal Cancer Trial, NCT01105169).