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We expressed human type I interferon (IFN) receptors (IFNAR) in mice and investigated their signaling. Using a hydrodynamics-based delivery method, vectors containing the genes for IFNAR1 and IFNAR2 were transferred into mice. Six hours after gene-transfer, mice were intravenously injected with human IFN-alpha at 10,000 IU. IFNAR1 and IFNAR2 were both expressed in the liver, but not spleen or lung. The receptors were coexpressed in single liver cells. One hour after IFN-alpha injection, the phosphorylation status of signal transducer and activator of transcription factor 1 (STAT1), a key molecule of IFN signaling, was determined. Phosphotyrosine-STAT1 (p-STAT1), localized to the nucleus of IFNAR-expressing cells, was increased in the livers of IFNAR gene-transferred mice but not in control vector-transferred animals. In conclusion, functional human IFNAR can be delivered to the mouse liver, resulting in an increase in p-STAT1 levels following human IFN-alpha stimulation.
Trisomy 21 (T21) causes Down syndrome (DS), affecting immune and neurological function by ill-defined mechanisms. Here we report a large metabolomics study of plasma and cerebrospinal fluid, showing in independent cohorts that people with DS produce elevated levels of kynurenine and quinolinic acid, two tryptophan catabolites with potent immunosuppressive and neurotoxic properties, respectively. Immune cells of people with DS overexpress IDO1, the rate-limiting enzyme in the kynurenine pathway (KP) and a known interferon (IFN)-stimulated gene. Furthermore, the levels of IFN-inducible cytokines positively correlate with KP dysregulation. Using metabolic tracing assays, we show that overexpression of IFN receptors encoded on chromosome 21 contribute to enhanced IFN stimulation, thereby causing IDO1 overexpression and kynurenine overproduction in cells with T21. Finally, a mouse model of DS carrying triplication of IFN receptors exhibits KP dysregulation. Together, our results reveal a mechanism by which T21 could drive immunosuppression and neurotoxicity in DS.
Although frequently expressed in Epstein-Barr virus (EBV)-positive malignancies, the role that latent membrane protein 2A and 2B (LMP2A and LMP2B) have in the oncogenic process remains obscure. Here we show a novel function for these proteins in epithelial cells, namely, their ability to modulate signalling from type I/II interferon receptors (IFNRs). We show that LMP2A- and LMP2B-expressing epithelial cells show decreased responsiveness to interferon (IFN)alpha and IFNgamma, as assessed by STAT1 phosphorylation, ISGF3 and GAF-mediated binding to IFN-stimulated response element and IFNgamma-activated factor sequence elements and luciferase reporter activation. Transcriptional profiling highlighted the extent of this modulation, with both viral proteins impacting 'globally' on IFN-stimulated gene expression. Although not affecting the levels of cell-surface IFNRs, LMP2A and LMP2B accelerated the turnover of IFNRs through processes requiring endosome acidification. This function may form part of EBV's strategy to limit anti-viral responses and define a novel function for LMP2A and LMP2B in modulating signalling from receptors that participate in innate immune responses.
Detection of intracellular DNA triggers activation of the STING-dependent interferon-stimulatory DNA (ISD) pathway, which is essential for antiviral responses. Multiple DNA sensors have been proposed to activate this pathway, including AIM2-like receptors (ALRs). Whether the ALRs are essential for activation of this pathway remains unknown. To rigorously explore the function of ALRs, we generated mice lacking all 13 ALR genes. We found that ALRs are dispensable for the type I interferon (IFN) response to transfected DNA ligands, DNA virus infection, and lentivirus infection. We also found that ALRs do not contribute to autoimmune disease in the Trex1(-/-) mouse model of Aicardi-Goutières Syndrome. Finally, CRISPR-mediated disruption of the human AIM2-like receptor IFI16 in primary fibroblasts revealed that IFI16 is not essential for the IFN response to human cytomegalovirus infection. Our findings indicate that ALRs are dispensable for the ISD response and suggest that alternative functions for these receptors should be explored.
While inhibition of T cell co-inhibitory receptors has revolutionized cancer therapy, the mechanisms governing their expression on human T cells have not been elucidated. Type 1 interferon (IFN-I) modulates T cell immunity in viral infection, autoimmunity, and cancer, and may facilitate induction of T cell exhaustion in chronic viral infection. Here we show that IFN-I regulates co-inhibitory receptor expression on human T cells, inducing PD-1/TIM-3/LAG-3 while surprisingly inhibiting TIGIT expression. High-temporal-resolution mRNA profiling of IFN-I responses enabled the construction of dynamic transcriptional regulatory networks uncovering three temporal transcriptional waves. Perturbation of key transcription factors on human primary T cells revealed unique regulators that control expression of co-inhibitory receptors. We found that the dynamic IFN-I response in vitro closely mirrored T cell features with IFN-I linked acute SARS-CoV-2 infection in human, with high LAG3 and decreased TIGIT expression. Finally, our gene regulatory network identified SP140 as a key regulator for differential LAG3 and TIGIT expression, which were validated at the level of protein expression. The construction of IFN-I regulatory networks with identification of unique transcription factors controlling co-inhibitory receptor expression may provide targets for enhancement of immunotherapy in cancer, infectious diseases, and autoimmunity.
While inhibition of T cell co-inhibitory receptors has revolutionized cancer therapy, the mechanisms governing their expression on human T cells have not been elucidated. Type 1 interferon (IFN-I) modulates T cell immunity in viral infection, autoimmunity, and cancer, and may facilitate induction of T cell exhaustion in chronic viral infection 1,2 . Here we show that IFN-I regulates co-inhibitory receptors expression on human T cells, inducing PD-1/TIM-3/LAG-3 while surprisingly inhibiting TIGIT expression. High-temporal-resolution mRNA profiling of IFN-I responses enabled the construction of dynamic transcriptional regulatory networks uncovering three temporal transcriptional waves. Perturbation of key transcription factors on human primary T cells revealed both canonical and non-canonical IFN-I transcriptional regulators, and identified unique regulators that control expression of co-inhibitory receptors. To provide direct in vivo evidence for the role of IFN-I on co-inhibitory receptors, we then performed single cell RNA-sequencing in subjects infected with SARS-CoV-2, where viral load was strongly associated with T cell IFN-I signatures. We found that the dynamic IFN-I response in vitro closely mirrored T cell features with acute IFN-I linked viral infection, with high LAG3 and decreased TIGIT expression. Finally, our gene regulatory network identified SP140 as a key regulator for differential LAG3 and TIGIT expression. The construction of co-inhibitory regulatory networks induced by IFN-I with identification of unique transcription factors controlling their expression may provide targets for enhancement of immunotherapy in cancer, infectious diseases, and autoimmunity.
Although inhibition of T cell coinhibitory receptors has revolutionized cancer therapy, the mechanisms governing their expression on human T cells have not been elucidated. In the present study, we show that type 1 interferon (IFN-I) regulates coinhibitory receptor expression on human T cells, inducing PD-1/TIM-3/LAG-3 while inhibiting TIGIT expression. High-temporal-resolution mRNA profiling of IFN-I responses established the dynamic regulatory networks uncovering three temporal transcriptional waves. Perturbation of key transcription factors (TFs) and TF footprint analysis revealed two regulator modules with different temporal kinetics that control expression of coinhibitory receptors and IFN-I response genes, with SP140 highlighted as one of the key regulators that differentiates LAG-3 and TIGIT expression. Finally, we found that the dynamic IFN-I response in vitro closely mirrored T cell features in acute SARS-CoV-2 infection. The identification of unique TFs controlling coinhibitory receptor expression under IFN-I response may provide targets for enhancement of immunotherapy in cancer, infectious diseases and autoimmunity.
Cytosolic DNAs derived from retrotransposons serve as pathogen-associated molecular patterns for pattern recognition receptors (PRRs) that stimulate the induction of interferons (IFNs) and other cytokines, leading to autoimmune disease. Cyclic GMP-AMP synthase is one PRR that senses retrotransposon DNA, activating type I IFN responses through the stimulator of IFN genes (STING). Absent in melanoma 2 (AIM2)-like receptors (ALRs) have also been implicated in these pathways. Here we show that the mouse ALR IFI205 senses cytosolic retrotransposon DNA independently of cyclic GMP-AMP production. AIM2 antagonizes IFI205-mediated IFN induction activity by sequestering it from STING. We also found that the complement of genes located in the ALR locus in C57BL/6 and AIM2 knockout mice are different and unique, which has implications for interpretation of the sensing of pathogens in different mouse strains. Our data suggest that members of the ALR family are critical to the host IFN response to endogenous DNA.IMPORTANCE Autoimmune diseases like Aicardi-Goutières syndrome and lupus erythematosus arise when cells of the immune system become activated and attack host cells and tissues. We found that DNA generated by endogenous retroviruses and retroelements in inbred mice and mouse cells is recognized by several host proteins found in macrophages that are members of the ALR family and that these proteins both suppress and activate the pathways leading to the generation of cytokines and IFNs. We also show that there is great genetic diversity between different inbred mouse strains in the ALR genes, which might contribute to differential susceptibility to autoimmunity. Understanding how immune cells become activated is important to the control of disease.
Nipah virus (NiV; genus: Henipavirus; family: Paramyxoviridae) naturally infects Old World fruit bats (family Pteropodidae) without causing overt disease. Conversely, NiV infection in humans and other mammals can be lethal. Comparing bat antiviral responses with those of humans may illuminate the mechanisms that facilitate bats' tolerance. Tripartite motif proteins (TRIMs), a large family of E3-ubiquitin ligases, fine-tune innate antiviral immune responses, and two human TRIMs interact with Henipavirus proteins. We hypothesize that NiV infection induces the expression of an immunosuppressive TRIM in bat, but not human cells, to promote tolerance. Here, we show that TRIM40 is an interferon-stimulated gene (ISG) in pteropodid but not human cells. Knockdown of bat TRIM40 increases gene expression of IFNβ, ISGs, and pro-inflammatory cytokines following poly(I:C) transfection. In Pteropus vampyrus, but not human cells, NiV induces TRIM40 expression within 16 h after infection, and knockdown of TRIM40 correlates with reduced NiV titers as compared to control cells. Bats may have evolved to express TRIM40 in response to viral infections to control immunopathogenesis.
Interferons (IFNs) are widely expressed cytokines with antiviral and immune-modulating effects and have been utilised for the treatment of several human pathological conditions. In particular, the immune-modulatory drug IFN-β is utilized in the treatment of multiple sclerosis (MS), a chronic autoimmune and neurodegenerative disorder of the central nervous system (CNS). Although the effects of IFN-β on immune cells functions have been widely investigated, information about the ability of the drug to modulate neuronal transmission in the CNS is still largely lacking. The aim of this study was to investigate the ability of IFN-β1a to modulate excitatory synaptic transmission in the CNS. Whole cell patch-clamp electrophysiological recordings were performed in the nucleus striatum, one of the CNS grey matter structures that is prone to degenerate during the course of MS. We demonstrate that the drug IFN-β1a, independently from its known peripheral immune-modulating action, is able to directly modulate synaptic transmission. In particular, we demonstrated that IFN-β1a reduces the amplitude of striatal excitatory post-synaptic currents, indicating an inhibitory effect on glutamate neurotransmission, and in particular on its NMDA component. The inhibitory effect of IFN-β1a on striatal glutamate neurotransmission was found to be mediated by a novel post-synaptic mechanism requiring Ca(2+), CaMKII and the GluN2A subunit of the NMDA receptor, without the involvement of the classic STAT1 pathway. The evidence of a novel neuro-modulating effect of IFN-β shed light on the mechanisms of action of the drug and on the complex bidirectional interaction occurring between the immune and the nervous system. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'.
Interferons (IFNs) are critical soluble factors in the immune system and are composed of three types, (I, II and III) that utilize different receptor complexes IFN-αR1/IFN-αR2, IFN-γR1/IFN-γR2, and IFN-λR1/IL-10R2, respectively. Here we identify IFN-υ from the genomic sequences of vertebrates. The members of class II cytokine receptors, IFN-υR1 and IL-10R2, are identified as the receptor complex of IFN-υ, and are associated with IFN-υ stimulated gene expression and antiviral activity in zebrafish (Danio rerio) and African clawed frog (Xenopus laevis). IFN-υ and IFN-υR1 are separately located at unique and highly conserved loci, being distinct from all other three-type IFNs. IFN-υ and IFN-υR1 are phylogenetically clustered with class II cytokines and class II cytokine receptors, respectively. Therefore, the finding of this IFN ligand-receptor system may be considered as a type IV IFN, in addition to the currently recognized three types of IFNs in vertebrates.
Interferon γ receptor 1 (IFNGR1) and IFNGR2 are two cell membrane molecules belonging to class II cytokines, which play important roles in the IFN-mediated antiviral signaling pathway. Here, goose IFNGR1 and IFNGR2 were cloned and identified for the first time. Tissue distribution analysis revealed that relatively high levels of goose IFNγ mRNA transcripts were detected in immune tissues, including the harderian gland, cecal tonsil, cecum, and thymus. Relatively high expression levels of both IFNGR1 and IFNGR2 were detected in the cecal tonsil, which implicated an important role of IFNγ in the secondary immune system of geese. No specific correlation between IFNγ, IFNGR1, and IFNGR2 expression levels was observed in the same tissues of healthy geese. IFNγ and its cognate receptors showed different expression profiles, although they appeared to maintain a relatively balanced state. Furthermore, the agonist R848 led to the upregulation of goose IFNγ but did not affect the expression of goose IFNGR1 or IFNGR2. In summary, trends in expression of goose IFNγ and its cognate receptors showed tissue specificity, as well as an age-related dependency. These findings may help us to better understand the age-related susceptibility to pathogens in birds.
The intestinal mucosa protects the body from physical damage, pathogens, and antigens. However, inflammatory bowel diseases (IBDs) patients suffer from poor mucosal tissue function, including the lack of an effective cellular and/or mucus barrier. We investigated the mucus producing human colonic epithelial cell line HT29-MTX E12 to study its suitability as an in vitro model of cell/mucus barrier adaption during IBD. It was found that the proinflammatory cytokine interferon-gamma (IFN-γ), but not tumor necrosis factor-alpha (TNF-α), reduced cell viability. IFN-γ and TNF-α were found to synergize to decrease barrier function, as measured by trans-epithelial electric resistance (TER) and molecular flux assays. Cells cultured under an air-liquid interface produced an adherent mucus layer, and under these conditions reduced barrier function was found after cytokine exposure. Furthermore, IFN-γ, but not TNF-α treatment, upregulated the IFN-γ receptor 1 (IFNGR1) and TNF-α receptor super family 1A (TNFRSF1A) subunit mRNA in vitro. Co-stimulation resulted in increased mRNA expression of CLDN 2 and 5, two gene known to play a role in epithelial barrier integrity. Analysis of IBD patient samples revealed IFNGR1 and TNFRSF mRNA increased coincidently with guanylate binding protein 1 (GBP1) expression, an indicator of NFkB activity. Lastly, CLDN2 was found at higher levels in IBD patients while HNF4a was suppressed with disease. In conclusion, IFN-γ and TNF-α degrade epithelial/mucus barriers coincident with changes in CLDN gene and cytokine receptor subunit mRNA expression in HT29-MTX E12 cells. These changes largely reflect those observed in IBD patient samples.
The role of inflammation in mood disorders has received increased attention. There is substantial evidence that cytokine therapies, such as interferon alpha (IFN-alpha), can induce depressive symptoms. Indeed, proinflammatory cytokines change brain function in several ways, such as altering neurotransmitters, the glucocorticoid axis, and apoptotic mechanisms. This study aimed to evaluate the impact on mood of initiating IFN-alpha and ribavirin treatment in a cohort of patients with chronic hepatitis C. We investigated clinical, personality, and functional genetic variants associated with cytokine-induced depression.
This study tested the hypothesis that a set of predominantly myeloid restricted receptors (F4/80, CD36, Dectin-1, CD200 receptor and mannan binding lectins) and the broadly expressed CD200 played a role in a key function of plasmacytoid DC (pDC), virally induced type I interferon (IFN) production. The Dectin-1 ligands zymosan, glucan phosphate and the anti-Dectin-1 monoclonal antibody (mAb) 2A11 had no effect on influenza virus induced IFNα/β production by murine splenic pDC. However, mannan, a broad blocking reagent against mannose specific receptors, inhibited IFNα/β production by pDC in response to inactivated influenza virus. Moreover, viral glycoproteins (influenza virus haemagglutinin and HIV-1 gp120) stimulated IFNα/β production by splenocytes in a mannan-inhibitable manner, implicating the function of a lectin in glycoprotein induced IFN production. Lastly, the effect of CD200 on IFN induction was investigated. CD200 knock-out macrophages produced more IFNα than wild-type macrophages in response to polyI:C, a MyD88-independent stimulus, consistent with CD200's known inhibitory effect on myeloid cells. In contrast, blocking CD200 with an anti-CD200 mAb resulted in reduced IFNα production by pDC-containing splenocytes in response to CpG and influenza virus (MyD88-dependent stimuli). This suggests there could be a differential effect of CD200 on MyD88 dependent and independent IFN induction pathways in pDC and macrophages. This study supports the hypothesis that a mannan-inhibitable lectin and CD200 are involved in virally induced type I IFN induction.
Recognition of microorganisms by the innate immune system is mediated by pattern recognition receptors, including Toll-like receptors and cytoplasmic RIG-I-like receptors. Chlamydia, which include several human pathogenic species, are obligate intracellular gram-negative bacteria that replicate in cytoplasmic vacuoles. The infection triggers a host response contributing to both bacterial clearance and tissue damage. For instance, type I interferons (IFN)s have been demonstrated to exacerbate the course of Chlamydial lung infections in mice.
A variety of data suggest that in vivo production of interferon (IFN)-gamma is necessary, but not sufficient, for expression of secondary protective immunity against intracellular pathogens. To discover specific IFN-gamma-independent T cell mediated mechanisms, we took advantage of an in vitro culture system that models in vivo immune responses to the intracellular bacterium Francisella tularensis live vaccine strain (LVS). LVS-immune lymphocytes specifically controlled 99% of the growth of LVS in wild-type murine bone marrow-derived macrophages. Surprisingly, LVS-immune lymphocytes also inhibited LVS intracellular growth by as much as 95% in macrophages derived from IFN-gamma receptor knockout (IFNgammaR KO) mice. CD8+ T cells, and to a lesser degree CD4+ T cells, controlled LVS intracellular growth in both wild-type and IFNgammaR KO macrophages. Further, a unique population of Thy1+alphabeta+CD4-CD8- cells that was previously suggested to operate during secondary immunity to LVS in vivo strongly controlled LVS intracellular growth in vitro. A large proportion of the inhibition of LVS intracellular growth in IFNgammaR KO macrophages by all three T cell subsets could be attributed to tumor necrosis factor (TNF) alpha. Thus, T cell mechanisms exist that control LVS intracellular growth without acting through the IFN-gamma receptor; such control is due in large part to TNF-alpha, and is partially mediated by a unique double negative T cell subpopulation.
An important function of immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptors is cross-regulation of heterologous receptor signaling, but mechanisms of cross-inhibition are poorly understood. We show that high-avidity ligation of ITAM-coupled beta2 integrins and FcgammaRs in macrophages inhibited type I interferon receptor and Toll-like receptor (TLR) signaling and induced expression of interleukin-10 (IL-10); signaling inhibitors SOCS3, ABIN-3, and A20; and repressors of cytokine gene transcription STAT3 and Hes1. Induction of inhibitors was dependent on a pathway composed of signaling molecules DAP12, Syk, and Pyk2 that coupled to downstream kinases p38 and MSKs and required integration of IL-10-dependent and -independent signals. ITAM-induced inhibitors abrogated TLR responses by cooperatively targeting distinct steps in TLR signaling. Inhibitory signaling was suppressed by IFN-gamma and attenuated in inflammatory arthritis synovial macrophages. These results provide an indirect mechanism of cross-inhibition of TLRs and delineate a signaling pathway important for deactivation of macrophages.
Mammalian type I interferons (IFNs) signal through a receptor composed of the IFNAR1 and IFNAR2 chains. In zebrafish two-cysteine IFNs utilize a receptor composed of CRFB1 and CRFB5, while four-cysteine IFNs signal through a receptor formed by CRFB2 and CRFB5. In the present work two CRFB clusters were identified in different chromosomes of Atlantic salmon. Genes of three CRFB5s, one CRFB1, one CRFB2 and the novel CRFB5x were identified, cloned and studied functionally. All CRFBs were expressed in 10 different organs, but the relative expression of CRFBs varied. Mx-reporter assay was used to study which CRFBs might be involved in receptors for salmon IFNa, IFNb and IFNc. The results of Mx-reporter assays suggest that IFNa signals through a receptor composed of CRFB1a as the long chain and either CRFB5a, CRFB5b or CRFB5c as the short chain; IFNc signals through a receptor with CRFB5a or CRFB5c as the short chain while IFNb may signal through a receptor with CRFB5x as a short chain. Taken together, the present work demonstrates that Atlantic salmon has a more diverse repertoire of type I IFN receptors compared to zebrafish or mammals.
Triggering receptors expressed on myeloid cells (Trem) proteins are a family of cell surface receptors used to control innate immune responses such as proinflammatory cytokine production in mice. Trem genes belong to a rapidly expanding family of receptors that include activating and inhibitory paired-isoforms.
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