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Monday Article #39: Regulation of Type I interferon Signaling in Immune Response

Interferons (IFNs) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing the neighbouring cells to produce their anti-viral defences. (De Andrea M, Ravera R, Gioia D, Gariglio M, Landolfo S, 2002). IFNs belong to the large class of proteins known as cytokines molecules used for the communication between cells to trigger the immune system. “Interferon” named is derived from their ability to interfere with viral-replication. (Parkin J, Cohen B, 2001).


There are more than twenty various IFN genes and proteins have been discovered in animals including humans. They are typically divided into three major classes: Type I IFN, Type II IFN and Type III IFNs which are significant for fighting viral infections and for the regulation of the immune system.



Type I interferons (IFN-1) were first discovered over 60 years ago in a classical experiment by Isaacs and Lindenman in 1957, who showed that IFN-1s possess antiviral activity. Later, it became one of the first approved protein drugs using heterologous protein expression systems, which allowed its large-scale production. It has been approved and widely used in pleiotropy of diseases, including multiple-sclerosis, hepatitis B and C and some forms of cancer. (Schreiber, 2020)


Type I interferons (IFNs) are polypeptides that are secreted by viral-infected cells and have three major functions. First, they induce cell-intrinsic antimicrobial states in infected and neighbouring cells that limit the spread of infectious agents, particularly viral pathogens. Second, they modulate innate immune responses in a balanced manner that promotes antigen presentation and natural killer cell functions while restraining pro-inflammatory pathways and cytokine production. Third, they activate the adaptive immune system, thus promoting the development of high-affinity antigen-specific T and B cell responses and immunological memory. (Trinchieri, 2010)


Type I interferons (IFN-1) 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. (Lionel B. Ivashkiv & Laura T. Donlin, 2014)


Figure 1 focuses on the most well-defined type I IFNs, namely IFN alpha and IFN beta. Most cell types produce IFN, while haematopoietic cells, particularly plasmacytoid dendrite cells, are the predominant producers of IFNa. IFNb is encoded by a single IFNB gene, whereas 14 distinct genes encode various IFNa isoforms. Type IFN-1 production is induced after the triggering of microbial products by pattern-recognition receptors (PRRs) and by cytokines. (Lionel B. Ivashkiv & Laura T. Donlin, 2014)


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 cells, such as macrophages and dendrite cells (DCs), produce type I IFNs after sensing pathogen components using various pattern-recognition receptors (PRRs), which are found on their plasma membrane, in endosomes and throughout cytosol. In particular, plasmacytoid DCs (pDCs) produce large quantities of IFNa. Non-immune cells, such as fibroblasts and epithelial cells, predominantly produce IFNb. 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. (Lionel B. Ivashkiv & Laura T. Donlin, 2014)


IFN alpha and IFN beta binds a heterodimeric transmembrane receptor; IFN alpha/beta receptor (IFNAR) which composed of IFNAR1 and IFNAR2 subunits. In the canonical type 1 IFN-induced signalling pathway, IFNAR engagement was shown to activate the receptor-associated protein tyrosine kinases; Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2), which then will phosphorylate signal transducer and activator of transcriptions; (STAT1) and (STAT2). (Lionel B. Ivashkiv & Laura T. Donlin, 2014)


Figure 2 The canonical type 1 interferon signalling pathway


Phosphorylation of the receptor by JAK1 and TYK2 results in the recruitment of signal transducer and activator of transcription (STAT) proteins, phosphorylation and dimerization and nuclear translocation. The three predominant STAT complexes (STAT1, STAT2 and STAT3) that are formed in response to type 1 interferon (IFN) control distinct gene-expression programmes. (Lionel B. Ivashkiv & Laura T. Donlin, 2014)


1. The interferon-stimulated gene factor 3 (ISGF3) complex which composed of STAT1, STAT2 and IFN-regulatory factor 9 (IRF9) binds to IFN-stimulated responses element (ISRE) sequences to activate classical antiviral genes.

2. STAT1 homodimers bind to gamma-activated sequences (GAGs) to induce pro-inflammatory genes.

3. STAT3 homodimers indirectly suppress pro-inflammatory gene expression, by the induction of as- yet-unknown transcriptional repressors. Type 1 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.




References:


1. Schreiber, G. (2020). The Role of Type I Interferons in the Pathogenesis and Treatment of COVID-19. Retrieved from Frontiers in Immunology: https://www.frontiersin.org/articles/10.3389/fimmu.2020.595739/full


2. De Andrea M, Ravera R, Gioia D, Gariglio M, Landolfo S. (2002). The interferon system: an overview. Retrieved from ScienceDirect : https://www.sciencedirect.com/science/article/pii/S1090379802905738?via%3Dihub


3. Lionel B. Ivashkiv & Laura T. Donlin. (2014). Regulation of type I interferon responses. Retrieved from Nature reviews immunology: https://www.nature.com/articles/nri3581


4. Parkin J, Cohen B. (2001). An overview of the immune system. Retrieved from National Library of Medicine: https://pubmed.ncbi.nlm.nih.gov/11403834/


5. Trinchieri, G. (2010). Type I interferon: friend or foe? Retrieved from National Library of Medicine: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947062/.


 

This article was prepared by Emeralda Erna Nordin

 







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