Shared and Distinct Functions of Type I and Type III Interferons

Abstract

Type I interferons (IFNs) (IFN-α, IFN-β) and type III IFNs (IFN-λ) share many properties, including induction by viral infection, activation of shared signaling pathways, and transcriptional programs. However, recent discoveries have revealed context-specific functional differences. Here, we provide a comprehensive review of type I and type III IFN activities, highlighting shared and distinct features from molecular mechanisms through physiological responses. Beyond discussing canonical antiviral functions, we consider the adaptive immune priming, anti-tumor, and autoimmune functions of IFNs. We discuss a model wherein type III IFNs serve as a front-line defense that controls infection at epithelial barriers while minimizing damaging inflammatory responses, reserving the more potent type I IFN response for when local responses are insufficient. In this context, we discuss current therapeutic applications targeting these cytokine pathways and highlight gaps in understanding of the biology of type I and type III IFNs in health and disease.

Figure 1.. Canonical Type I and Type III IFN Signaling

Type I and type III IFNs bind to distinct receptors but activate similar signaling pathways and transcriptional responses. The type I and type III IFN receptors are heterodimers comprised of IFNAR1 and IFNAR2 subunits or IFNLR1 and IL10Rβ subunits, respectively. IFNs first bind one receptor chain with high affinity (IFNAR2 or IFNLR1), then recruit a low-affinity receptor chain (IFNAR1 or IL10Rβ) to create a signaling-competent ternary complex. Receptor dimerization activates TYK2 and JAK1 kinases, which phosphorylate STAT1 and STAT2. Phosphorylated STAT1 and STAT2 heterodimers complex with IRF9 to produce the transcription factor ISGF3. ISGF3 binds to ISREs and promotes expression of hundreds of ISGs. Type I and type III IFNs also activate additional signaling pathways not depicted in this figure.

Figure 2.. Comparison of Type I and Type III IFNs

Although their signaling pathways and transcriptional responses have many similarities, some features distinguish type I and type III IFNs: (1) most type I IFN genes lack introns, whereas type III IFN genes have 5 or 6 exons; (2) the type I IFN family is larger, comprising 17 members in humans and 18 in mice, compared with 4 type III IFN members in humans and 2 in mice; (3) type I and type III IFNs bind distinct receptors. The type I IFN receptor (IFNAR) is ubiquitously expressed, whereas the type III IFN receptor (IFNLR) is expressed preferentially on epithelial cells, as well as neutrophils; (4) although the genes activated by type I and type III IFN signaling are similar, differences in cell type specificity and signaling kinetics result in distinct responses. The type I IFN response is more potent, rapid, and transient, whereas the type III IFN response is less potent, slower, and sustained. Many cell types respond to type I IFNs, resulting in a systemic response that is more inflammatory. In contrast, the type III IFN response is less inflammatory and concentrated at epithelial and barrier surfaces.

Figure 3.. Induction and Antiviral Signaling of Type I and Type III IFNs

(A and B) Type I IFNs (A) and type III IFNs(B) are both induced when viral infection is detected by PRRs including RIG-I like receptors (RLRs), Toll-like receptors (TLRs), and cGAS (not depicted). Differences in the subcellular localization of the PRR response can favor production of type III over type I IFNs (e.g., plasma membrane TLR4 signaling or peroxisomal MAVS signaling). PRR signaling activates IRF-family transcription factors which, together with NFκB, promote IFN expression. IFNs are secreted by infected cells and signal in a paracrine manner to uninfected cells to stimulate the production of ISGs, which act by a variety of mechanisms to induce an antiviral state. Among the ISGs induced by IFN signaling are other IFNs, resulting in a positive feedback loop of antiviral activity.