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Regulation of type I interferon responses

Key Points

  • Type I interferon (IFN) responses are regulated by host, pathogen and environmental factors. These factors calibrate the host defences while limiting tissue damage and preventing autoimmunity.

  • Type I IFNs signal via the IFNα receptor (IFNAR) to activate receptor-associated Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2) kinases and downstream signal transducer and activator of transcription (STAT) transcription factors; these transcription factors then induce the expression of IFN-stimulated genes (ISGs). Type I IFNs activate the IFN-stimulated gene factor 3 (ISGF3) complex, which is comprised of STAT1, STAT2 and IFN-regulatory factor 9 (IRF9); the ISGF3 complex binds to IFN-stimulated response elements (ISREs) to induce the expression of antiviral genes.

  • Type I IFN signalling is regulated in a quantitative and qualitative manner. The magnitude of signalling is increased by induction of STAT1 and IRF9 expression and amplification of JAK signalling by spleen tyrosine kinase (SYK) and protein tyrosine kinase 2 (PYK2). Conversely, the magnitude of signalling is decreased by suppressor of cytokine signalling (SOCS) and ubiquitin carboxy-terminal hydrolase 18 (USP18) proteins and by the downregulation and internalization of IFNAR. The qualitative nature of type I IFN responses is determined by the balance between the activation of various STATs and ISGF3.

  • Type I IFN-induced transcription is regulated by the post-translational modification of STATs, chromatin remodelling, the epigenetic landscape and cooperation with other transcription factors, co-activators and co-repressors.

  • ISGs encode proteins that regulate the translation of IFNAR and JAK–STAT signalling components and of ISGs themselves. Type I IFNs also induce the expression of microRNAs that regulate the IFN response.

  • Chronic type I IFN responses can promote autoimmunity by increasing antigen presentation, lymphocyte-mediated adaptive immune responses and chemokine expression. In chronic infections, type I IFNs can induce immunosuppression in part by increasing expression of interleukin-10 and programmed cell death 1 ligand 1 (PDL1).

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.

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Figure 1: Type I interferon controls innate and adaptive immunity and intracellular antimicrobial programmes.
Figure 2: The canonical type I interferon signalling pathway.
Figure 3: Type I interferon signalling is regulated by heterologous pathways.
Figure 4: Type I interferon induction of interferon-stimulated genes involves chromatin remodelling and recruitment of various transcriptional activators.
Figure 5: Persistent type I interferon exposure in autoimmune disease and chronic infection induces immunosuppressive pathways.

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Acknowledgements

We thank P. Crow for critical review of the manuscript. This work was supported by grants from the US National Institutes of Health.

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Correspondence to Lionel B. Ivashkiv.

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Glossary

MicroRNAs

(miRNAs). Small RNA molecules that regulate the expression of genes by binding to the 3′ untranslated regions of specific mRNAs.

Degron sequence

Degrons are signals within proteins that target them for rapid degradation. Degrons can be overt, as in the case of the N-end rule, or covert, as in the case of cyclins. For example, cyclin B must be rapidly destroyed after mitosis, and this is achieved by kinase-regulated access to a 'destruction box' sequence in cyclin B that stimulates polyubiquitylation and subsequent degradation by the proteasome.

Mediator

A multiprotein complex that functions as a co-activator of transcription in all eukaryotes.

Sumoylated

A sumoylated protein has undergone a type of post-translational protein modification in which the ubiquitin-like protein SUMO (small ubiquitin-related modifier) is covalently attached to the protein by an enzymatic cascade that is analogous to the cascade involved in protein ubiquitylation.

CpG islands

Sequences of 0.5–2 kilobases that are rich in CpG dinucleotides. They are mostly located upstream of housekeeping genes and also of some tissue-specific genes. They are constitutively hypomethylated in many animal cell types.

RVB proteins

ATP-binding proteins that belong to the ATPase- associated with diverse cellular activities (AAA) family of ATPases. They are found in different protein and nucleoprotein complexes that have roles in diverse cellular responses, including transcription, mitosis, development, apoptosis and DNA damage responses.

IFN signature

A pattern of increased expression of interferon- stimulated genes (ISGs) in tissue samples or stimulated cells. The IFN signature is typically detected by using a high-throughput approach, such as microarray or RNA sequencing, to analyse gene expression.

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Ivashkiv, L., Donlin, L. Regulation of type I interferon responses. Nat Rev Immunol 14, 36–49 (2014). https://doi.org/10.1038/nri3581

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