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Microbial nucleic acid recognition serves as the major stimulus to an antiviral response, implying a requirement to limit the misrepresentation of self nucleic acids as non-self and the induction of autoinflammation. By systematic screening using a panel of interferon-stimulated genes we identify two siblings and a singleton variably demonstrating severe neonatal anemia, membranoproliferative glomerulonephritis, liver fibrosis, deforming arthropathy and increased anti-DNA antibodies. In both families we identify biallelic mutations in DNASE2 , associated with a loss of DNase II endonuclease activity. We record increased interferon alpha protein levels using digital ELISA, enhanced interferon signaling by RNA-Seq analysis and constitutive upregulation of phosphorylated STAT1 and STAT3 in patient lymphocytes and monocytes. A hematological disease transcriptomic signature and increased numbers of erythroblasts are recorded in patient peripheral blood, suggesting that interferon might have a particular effect on hematopoiesis. These data define a type I interferonopathy due to DNase II deficiency in humans. Nucleic acid sensing is important to ensure that an innate immune response is only mounted against microbial nucleic acid. Here, the authors identify loss-of-function mutations in the DNASE2 gene that cause type I interferon-mediated autoinflammation due to enhanced systemic interferon signaling.

Heart disease link to inflammatory signalling A non-coding region on chromosome 9p21 was previously shown to associate with coronary artery disease and type 2 diabetes, and the region has been implicated in regulating neighbouring genes. Here the authors identify 33 distinct enhancers within this region and show that single nucleotide polymorphisms in one of the enhancers affect STAT1 binding. They further show that in human vascular endothelium cells, the enhancer interval physically interacts with a number of specific loci, and that interferon-γ activation strongly affects the chromatin structure and transcriptional regulation of the 9p21 locus, including STAT1 binding, long-range enhancer interactions and expression of neighbouring genes. A non-coding region on chromosome 9p21 was previously shown to associate with coronary artery disease and type 2 diabetes, and the region has been implicated in regulating neighbouring genes. Here, 33 distinct enhancers within this region are identified, showing that SNPs in one of the enhancers affect STAT1 binding. Furthermore, it is shown that in human vascular endothelial cells the enhancer interval physically interacts with a number of specific loci and that IFN-γ activation strongly affects the chromatin structure and transcriptional regulation of the 9p21 locus, including STAT1 binding, long-range enhancer interactions and expression of neighbouring genes. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in the 9p21 gene desert associated with coronary artery disease (CAD) 1 , 2 , 3 , 4 and type 2 diabetes 5 , 6 , 7 . Despite evidence for a role of the associated interval in neighbouring gene regulation 8 , 9 , 10 , the biological underpinnings of these genetic associations with CAD or type 2 diabetes have not yet been explained. Here we identify 33 enhancers in 9p21; the interval is the second densest gene desert for predicted enhancers and six times denser than the whole genome ( P  < 6.55 × 10 −33 ). The CAD risk alleles of SNPs rs10811656 and rs10757278 are located in one of these enhancers and disrupt a binding site for STAT1. Lymphoblastoid cell lines homozygous for the CAD risk haplotype show no binding of STAT1, and in lymphoblastoid cell lines homozygous for the CAD non-risk haplotype, binding of STAT1 inhibits CDKN2BAS (also known as CDKN2B-AS1 ) expression, which is reversed by short interfering RNA knockdown of STAT1 . Using a new, open-ended approach to detect long-distance interactions, we find that in human vascular endothelial cells the enhancer interval containing the CAD locus physically interacts with the CDKN2A/B locus, the MTAP gene and an interval downstream of IFNA21 . In human vascular endothelial cells, interferon-γ activation strongly affects the structure of the chromatin and the transcriptional regulation in the 9p21 locus, including STAT1-binding, long-range enhancer interactions and altered expression of neighbouring genes. Our findings establish a link between CAD genetic susceptibility and the response to inflammatory signalling in a vascular cell type and thus demonstrate the utility of genome-wide association study findings in directing studies to novel genomic loci and biological processes important for disease aetiology.

The efficacy of anticancer treatments, including radiotherapy, depends on the activation of type I IFN signaling. However, its regulatory networks and mechanisms remain to be elucidated. Here, we report that tumor cell-intrinsic type I IFN signaling can be transferred to macrophages via secretory autophagy, inducing CXCL9hi macrophages and enhancing CD8+ T cell-mediated antitumor immunity. Mechanistically, K63-linked ubiquitination at the K167 site of phosphorylated STAT2 (p-STAT2) facilitates its binding to LC3B, promoting the loading of p-STAT1 and p-STAT2 into extracellular vesicles and intercellular transference from tumor cells to macrophages, which, however, is suppressed by USP5-mediated STAT2 deubiquitination. Genetic depletion or pharmacological inhibition of USP5 promotes autophagy-dependent unconventional protein secretion of p-STAT1 and p-STAT2, leading to the induction of CXCL9+ macrophages. This process promotes the expression of T cell chemokines and upregulates the antigen presentation machinery, thereby enhancing radiation-induced CD8+ T cell antitumor immunity and radiotherapy efficacy. Our findings reveal a critical role of USP5 in type I IFN-induced antitumor immunity, providing potential targets for improving the efficacy of radiotherapy.

Positively selected thymocytes require a maturation phase before emigrating from the thymus. Hogquist and colleagues show that functional maturation is driven by tonic signals provided by type I interferons and the transcription factor NF-κB. Positive selection occurs in the thymic cortex, but critical maturation events occur later in the medulla. Here we defined the precise stage at which T cells acquired competence to proliferate and emigrate. Transcriptome analysis of late gene changes suggested roles for the transcription factor NF-κB and interferon signaling. Mice lacking the inhibitor of NF-κB (IκB) kinase (IKK) kinase TAK1 underwent normal positive selection but exhibited a specific block in functional maturation. NF-κB signaling provided protection from death mediated by the cytokine TNF and was required for proliferation and emigration. The interferon signature was independent of NF-κB; however, thymocytes deficient in the interferon-α (IFN-α) receptor IFN-αR showed reduced expression of the transcription factor STAT1 and phenotypic abnormality but were able to proliferate. Thus, both NF-κB and tonic interferon signals are involved in the final maturation of thymocytes into naive T cells.

Epithelial surfaces are the main entry point for viruses and thus are important immunological sites. Diefenbach and colleagues show that the related cytokines IL-22 and IFN-λ act together in the control of enterovirus infection. The epithelium is the main entry point for many viruses, but the processes that protect barrier surfaces against viral infections are incompletely understood. Here we identified interleukin 22 (IL-22) produced by innate lymphoid cell group 3 (ILC3) as an amplifier of signaling via interferon-λ (IFN-λ), a synergism needed to curtail the replication of rotavirus, the leading cause of childhood gastroenteritis. Cooperation between the receptor for IL-22 and the receptor for IFN-λ, both of which were 'preferentially' expressed by intestinal epithelial cells (IECs), was required for optimal activation of the transcription factor STAT1 and expression of interferon-stimulated genes (ISGs). These data suggested that epithelial cells are protected against viral replication by co-option of two evolutionarily related cytokine networks. These data may inform the design of novel immunotherapy for viral infections that are sensitive to interferons.

Long non-coding RNAs (lncRNAs) are pivotal regulators of cellular processes. Here we reveal an interaction between the lncRNA NORAD, noted for its role in DNA stability, and the immune related transcription factor STAT3 in embryonic and differentiated human cells. Results from NORAD knockdown experiments implicate NORAD in facilitating STAT3 nuclear localization and suppressing antiviral gene activation. In NORAD-deficient cells, STAT3 remains cytoplasmic, allowing STAT1 to enhance antiviral activity. Analysis of RNA expression data from in vitro experiments and clinical samples demonstrates reduced NORAD upon viral infection. Additionally, evolutionary conservation analysis suggests that this regulatory function of NORAD is restricted to humans, potentially owing to the introduction of an Alu element in hominoids. Our findings thus suggest that NORAD functions as a modulator of STAT3-mediated immune suppression, adding to the understanding of lncRNAs in immune regulation and evolutionary adaptation in host defense mechanisms. Long non-coding RNA (lncRNA) has diverse functions. Here the authors show that a lncRNA, NORAD, interacts with an immune transcription factor, STAT3, to facilitate STAT3 nuclear import and thereby modulating the intranuclear balance between STAT3 and STAT1 and the downstream activation of anti-viral immunity in vitro.

Radiotherapy (RT) combined with immune checkpoint inhibitors has recently produced outstanding results and is expected to be adaptable for various cancers. However, the precise molecular mechanism by which immune reactions are induced by fractionated RT is still controversial. We aimed to investigate the mechanism of the immune response regarding multifractionated, long‐term radiation, which is most often combined with immunotherapy. Two human esophageal cancer cell lines, KYSE‐450 and OE‐21, were irradiated by fractionated irradiation (FIR) daily at a dose of 3 Gy in 5 d/wk for 2 weeks. Western blot analysis and RNA sequencing identified type I interferon (IFN) and the stimulator of IFN genes (STING) pathway as candidates that regulate immune response by FIR. We inhibited STING, IFNAR1, STAT1, and IFN regulatory factor 1 (IRF1) and investigated the effects on the immune response in cancer cells and the invasion of surrounding immune cells. We herein revealed type I IFN‐dependent immune reactions and the positive feedback of STING, IRF1, and phosphorylated STAT1 induced by FIR. Knocking out STING, IFNAR1, STAT1, and IRF1 resulted in a poorer immunological response than that in WT cells. The STING‐KO KYSE‐450 cell line showed significantly less invasion of PBMCs than the WT cell line under FIR. In the analysis of STING‐KO cells and migrated PBMCs, we confirmed the occurrence of STING‐dependent immune activation under FIR. In conclusion, we identified that the STING‐IFNAR1‐STAT1‐IRF1 axis regulates immune reactions in cancer cells triggered by FIR and that the STING pathway also contributes to immune cell invasion of cancer cells. We elucidated that the fractionated irradiation‐induced immune response is regulated by the STING‐IFNAR1‐STAT1‐IRF1 pathway, which includes positive feedback, and that this mechanism acts not only on cancer cells but also on surrounding PBMCs.

The roles of individual microRNAs in the CD8 + T cell response remain mostly unexplored. Katsikis and colleagues show that miR-155 regulates type I interferon responsiveness and CD8 + T cell responses to pathogens in vivo . We found upregulation of expression of the microRNA miR-155 in primary effector and effector memory CD8 + T cells, but low miR-155 expression in naive and central memory cells. Antiviral CD8 + T cell responses and viral clearance were impaired in miR-155-deficient mice, and this defect was intrinsic to CD8 + T cells, as miR-155-deficient CD8 + T cells mounted greatly diminished primary and memory responses. Conversely, miR-155 overexpression augmented antiviral CD8 + T cell responses in vivo . Gene-expression profiling showed that miR-155-deficient CD8 + T cells had enhanced type I interferon signaling and were more susceptible to interferon's antiproliferative effect. Inhibition of the type I interferon–associated transcription factors STAT1 or IRF7 resulted in enhanced responses of miR-155-deficient CD8 + T cells in vivo . We have thus identified a previously unknown role for miR-155 in regulating responsiveness to interferon and CD8 + T cell responses to pathogens in vivo .

Aspergillus fumigatus is the most common cause of invasive aspergillosis (IA), a devastating infection in immunocompromised patients. Plasmacytoid DCs (pDCs) regulate host defense against IA by enhancing neutrophil antifungal properties in the lung. Here, we define the pDC activation trajectory during A. fumigatus infection and the molecular events that underlie the protective pDC-neutrophil crosstalk. Fungus-induced pDC activation began after bone marrow egress and resulted in pDC-dependent regulation of lung type I and type III IFN levels. These pDC-derived products acted on type I and type III IFN receptor-expressing neutrophils and controlled neutrophil fungicidal activity and ROS production via STAT1 signaling in a cell-intrinsic manner. Mechanistically, neutrophil STAT1 signaling regulated transcription and expression of Cybb, which encodes one of 5 NADPH oxidase subunits. Thus, the results indicate that pDCs regulate neutrophil-dependent immunity against inhaled molds by controlling local expression of a subunit required for NADPH oxidase assembly and activity in the lung.