Regulation of type I interferon responses

Abstract

Type I interferons (IFNs) activate intracellular antimicrobial programmes and influence the development of innate and adaptive immune responses. Canonical type I IFN signalling activates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, leading to transcription of IFN-stimulated genes (ISGs). Host, pathogen and environmental factors regulate the responses of cells to this signalling pathway and thus calibrate host defences while limiting tissue damage and preventing autoimmunity. Here, we summarize the signalling and epigenetic mechanisms that regulate type I IFN-induced STAT activation and ISG transcription and translation. These regulatory mechanisms determine the biological outcomes of type I IFN responses and whether pathogens are cleared effectively or chronic infection or autoimmune disease ensues.

Figure 1. Type I interferon controls innate and adaptive immunity and intracellular antimicrobial programmes

On pathogen detection, infected cells produce type I interferons (IFNs). Innate immune cells, such as macrophages and dendritic cells (DCs), produce type I IFNs after sensing pathogen components using various pattern-recognition receptors (PRRs), which are found on the plasma membrane, in endosomes and throughout the cytosol. In particular, plasmacytoid DCs (pDCs) produce large quantities of IFNα. Non-immune cells, such as fibroblasts and epithelial cells, predominantly produce IFNβ. In infected and neighbouring cells, type I IFNs induce the expression of IFN-stimulated genes (ISGs), the products of which initiate an intracellular antimicrobial programme that limits the spread of infectious agents. Innate immune cells also respond to type I IFNs by enhancing antigen presentation and the production of immune response mediators, such as cytokines and chemokines. Adaptive immunity is also affected by type I IFNs: for example, type I IFNs can augment antibody production by B cells and amplify the effector function of T cells. PAMP, pathogen-associated molecular pattern.

Figure 2. The canonical type I interferon signalling pathway

On engagement, the interferon-α receptor (IFNAR, which is composed of the IFNAR1 and IFNAR2 subunits) activates Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2). Phosphorylation of the receptor by these kinases results in the recruitment of signal transducer and activator of transcription (STAT) proteins, phosphorylation, dimerization and nuclear translocation. The three predominant STAT complexes that are formed in response to type I interferon (IFN) control distinct gene-expression programmes. The interferon-stimulated gene factor 3 (ISGF3) complex (which is composed of STAT1, STAT2 and IFN-regulatory factor 9 (IRF9)) binds to IFN-stimulated response element (ISRE) sequences to activate classical antiviral genes, whereas STAT1 homodimers bind to gamma-activated sequences (GASs) to induce pro-inflammatory genes. STAT3 homodimers indirectly suppress pro-inflammatory gene expression, probably by the induction of as-yet-unknown transcriptional repressors. Type I IFN-activated STAT3 is bound by the co-repressor complex SIN3 transcription regulator homologue A (SIN3A), which suppresses induction of direct STAT3 target genes by promoting de-acetylation of STAT3 and histones. Type I IFNs also activate STAT4 and can activate STAT5 and STAT6 in a context-dependent manner (not depicted). CXCL9, CXC-chemokine ligand 9; MX1, IFN-induced GTP-binding protein Mx1; OAS, 2′-5′-oligoadenylate synthase; P, phosphate.

Figure 3. Type I interferon signalling is regulated by heterologous pathways

Various receptor pathways cross-regulate the type I interferon (IFN) response; this alters the expression levels and activation states of IFN signalling components. Various mitogen-activated protein kinase (MAPK)-activating pathways, such as those induced by pattern-recognition receptors (PRRs), enhance signal transducer and activator of transcription 1 (STAT1) transcriptional activity through phosphorylation of a conserved carboxy-terminal serine. Low-level basal signalling by immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors also augments Janus kinase 1 (JAK1) activity through activation of spleen tyrosine kinase (SYK) and protein tyrosine kinase 2 (PYK2). Conversely, strong activation of ITAM-containing receptors by high-avidity crosslinking suppresses IFNα receptor (IFNAR) signalling via protein kinase C (PKC)-mediated recruitment of SH2 domain-containing protein-tyrosine phosphatase 2 (SHP2), which dephosphorylates signalling intermediates. Cytokine signalling pathways, including the interleukin-1 (IL-1) pathway, inhibit type I IFN responses by directly promoting IFN receptor turnover via p38 kinase and casein kinase II (CK2). Various cytokines that signal through JAK–STAT pathways, including type I IFNs, regulate the expression levels of both positive and negative regulators of the IFN response pathways. JAK–STAT-induced positive regulators include STAT1 and IFN-regulatory factor 9 (IRF9), whereas negative regulators include the suppressor of cytokine signalling (SOCS) protein family and ubiquitin carboxy-terminal hydrolase 18 (USP18). Inhibitor of NF-κB kinase-ε (IKKε)-mediated STAT1 phosphorylation inhibits STAT1 homodimerization, thereby promoting activation of the IFN-stimulated gene factor 3 (ISGF3) complex rather than STAT1 homodimers in response to type I IFN. IKKε expression is induced by various pathways, including tumour necrosis factor (TNF)- and PRR-induced pathways. MicroRNAs induced by cytokine and PRR pathways downregulate the expression of IFN response signalling proteins: for example, miR-146a suppresses STAT1 expression, and miR-155 causes a collective reduction in various IFN signalling proteins. AGO2, Argonaute 2; RISC, RNA-induced silencing complex.

Figure 4. Type I interferon induction of interferon-stimulated genes involves chromatin remodelling and recruitment of various transcriptional activators

In unstimulated cells, interferon-stimulated gene (ISG) transcription is suppressed by repressive transcription factors such as forkhead box protein O3 (FOXO3), high nucleosome occupancy due to low GC nucleotide content and repressive complexes bound to methylated histones. On type I interferon (IFN) stimulation, the IFN-stimulated gene factor 3 (ISGF3) complex (which contains signal transducer and activator of transcription 1 (STAT1), STAT2 and IFN-regulatory factor 9 (IRF9)) binds to ISG promoters and enhancers, recruiting various chromatin remodelling and transcriptional activator complexes. These complexes include the CREB-binding protein (CBP) histone acetyltransferase, the BRG1 chromatin remodelling factor, the multi-subunit Mediator co-activator complex, the Pol II-associated factor 1 homologue (PAF1) elongation factor and bromodomain-containing proteins (BRDs) such as BRD4 that bind to acetylated histones. BRDs recruit positive transcription elongation factor b (pTEFb), which augments transcription by phosphorylating RNA polymerase II (Pol II). CDK8, cyclin-dependent kinase 8; EHMT1, euchromatic histone-lysine N-methyltransferase 1; H4ac, histone H4 acetylation; H3K9me2; histone H3 lysine 9 dimethylation.

Figure 5. Persistent type I interferon exposure in autoimmune disease and chronic infection induces immunosuppressive pathways

a | In autoimmune diseases such as systemic lupus erythematosus (SLE), chronic type I interferon (IFN) production is perpetuated in part by dysregulated or persistent stimulation of antigen-presenting cells (APCs), including plasmacytoid dendritic cells (pDCs), by immune complexes and by damage-associated molecular pattern molecules (DAMPs). Persistent type I IFN exposure results in increased T and B cell effector function, leading to autoantibody production and ultimately autoimmune disease. Chronic stimulation by immune complexes and DAMPs (and potentially IFNs) also increases monocyte production of interleukin-10 (IL-10), which suppresses innate and adaptive immunity. Type I IFNs can also suppress cytokine production by innate immune cells. Although type I IFNs are generally thought to promote some autoimmune diseases, such as SLE, their balancing suppressive role might be dominant in other autoimmune diseases such as multiple sclerosis. The immunosuppressive properties of type I IFNs might contribute to increased susceptibility to particular infections in SLE. b | During chronic viral or bacterial infections, cells continuously produce type I IFNs. Chronic type I IFN exposure of innate immune cells ultimately induces immunosuppressive pathways involving IL-10 and programmed cell death 1 ligand 1 (PDL1), which suppress the function of T cells and feed back to also suppress innate immune cells. In chronic lymphocytic choriomeningitis virus (LCMV) and Mycobacterium leprae infections, persistent type I IFN exposure suppresses effective pathogen clearance pathways involving IFNγ. IFNR, IFN receptor; PD1, programmed cell death 1.