Differential Regulation of Type I and Type III Interferon Signaling

Abstract

Interferons (IFNs) are very powerful cytokines, which play a key role in combatting pathogen infections by controlling inflammation and immune response by directly inducing anti-pathogen molecular countermeasures. There are three classes of IFNs: type I, type II and type III. While type II IFN is specific for immune cells, type I and III IFNs are expressed by both immune and tissue specific cells. Unlike type I IFNs, type III IFNs have a unique tropism where their signaling and functions are mostly restricted to epithelial cells. As such, this class of IFN has recently emerged as a key player in mucosal immunity. Since the discovery of type III IFNs, the last 15 years of research in the IFN field has focused on understanding whether the induction, the signaling and the function of these powerful cytokines are regulated differently compared to type I IFN-mediated immune response. This review will cover the current state of the knowledge of the similarities and differences in the signaling pathways emanating from type I and type III IFN stimulation.

Comprehensive single cell analysis of pandemic influenza A virus infection in the human airways uncovers cell-type specific host transcriptional signatures relevant for disease progression and pathogenesis

“…PRRs relevant to IAV, including Toll-like receptor 3 (TLR3), Melanoma differentiation-associated protein 5 (MDA5), and retinoic acid-inducible gene I (RIG-I), are known to be expressed under both naive and IFN-stimulated conditions in the human airway epithelium 17–20 . Upon recognition, PRRs bind to their cognate PAMPs and activate downstream signalling pathways that ultimately lead to the induction of both type I and III IFNs 21 . Notably, type III IFNs are particularly abundant at mucosal sites and play an important role in epithelial antiviral defence, whereas type I IFNs are expressed more ubiquitously in multiple host tissues 21 .…”

“…Upon recognition, PRRs bind to their cognate PAMPs and activate downstream signalling pathways that ultimately lead to the induction of both type I and III IFNs 21 . Notably, type III IFNs are particularly abundant at mucosal sites and play an important role in epithelial antiviral defence, whereas type I IFNs are expressed more ubiquitously in multiple host tissues 21 . Activation of either pathway leads to the upregulation of hundreds of IFN-stimulated genes (ISGs), as well as many pro-inflammatory cytokines and chemokines 13–16,21 .…”

Interferon Response in Hepatitis C Virus-Infected Hepatocytes: Issues to Consider in the Era of Direct-Acting Antivirals

“…When types I and III IFNs bind to their receptors, the intracellular receptor subunits undergo conformational changes to interact with Janus kinases (JAKs), which lead to the activation of the JAK/signal transducer and activator of transcription (STAT) pathway. The JAKs include JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2) [30]. The binding of both type I and type III IFNs to their respective receptor complexes leads to the phosphorylation of JAK1 and TYK2.…”

The potential of the combined use of targeted type I interferon pathway inhibitors and oncolytic viruses to treat sarcomas

“…A recent review of type I IFN signalling discusses the complexities of canonical and alternative pathways of IFN signalling . These pathways are very briefly summarized in Figure .…”

“…Indeed, it was shown several years ago that valproate (a JAK1 inhibitor) prevented the resistance of synovial cell sarcoma cells to VSV 51. How inhibition of the type I IFN pathway might improve the outcomes of OV therapy is the focus of this section.A recent review of type I IFN signalling discusses the complexities of canonical and alternative pathways of IFN signalling 52. These pathways are very briefly summarized inFigure 1.…”