Interferon-λ orchestrates innate and adaptive mucosal immune responses

Abstract

Type III interferon (IFN-λ) was initially thought to have functions similar to those of the type I interferons (IFN-α and IFN-β). New findings have indicated, however, that IFN-λ has a non-redundant role in the innate antiviral, antifungal and antiprotozoal defences of mucosal barriers. In this Review, we highlight recent work showing that IFN-λ inhibits virus dissemination within the body and limits the transmission of respiratory and gastrointestinal viruses to naive hosts. We also discuss findings indicating that IFN-λ can act on neutrophils to prevent invasive pulmonary aspergillosis. We summarize results showing that IFN-λ signalling differs in several respects from IFN-α and IFN-β signalling, particularly in neutrophils. Finally, we discuss new findings indicating that IFN-λ is a potent enhancer of adaptive immune responses in the respiratory mucosa.

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Fig. 1: Type I and type III IFN-induced signalling pathways.
Fig. 2: IFN-λ-induced production of reactive oxygen species in mouse neutrophils.
Fig. 3: IFN-λ induces innate immune defences at mucosal barriers.
Fig. 4: IFN-λ activates adaptive immune responses in the upper airways.

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Acknowledgements

The authors thank O. Haller for constructive comments on this article. Funding for the work carried out in the laboratory of the authors was provided by the European Union’s Seventh Framework Program, grant agreement 607690, and the Deutsche Forschungsgemeinschaft, grant agreement STA 338/15-1.

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Nature Reviews Immunology thanks S. Boulant, S. V. Kotenko and other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Janus kinase family

(JAK family). JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2) are non-receptor tyrosine kinases associated with class I and class II cytokine receptors that are responsible for signal transduction through the phosphorylation of signal transducer and activator of transcription (STAT) family members.

Signal transducer and activator of transcription

(STAT). STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6 are transcription factors that are activated by Janus kinases to transduce the signal from class I and class II cytokine receptors. Type I and type III interferons (IFNs) mainly induce the activation of STAT1–STAT2 heterodimers, which form a complex with IFN response factor 9 (IRF9), known as IFN-stimulated gene factor 3 (ISGF3). Type II IFN (IFN-γ) mainly induces the activation of STAT1 homodimers.

Interferon-stimulated gene factor 3

(ISGF3). A complex consisting of STAT1–STAT2 heterodimers, together with interferon (IFN) response factor 9 (IRF9). ISGF3 binds to IFN-stimulated response elements (ISREs) in the promoter regions of IFN-stimulated genes to regulate transcriptional activity.

Interferon-stimulated response element

(ISRE). A sequence element in the promoter regions of interferon-stimulated genes (ISGs) that is recognized by ISG factor 3 (ISGF3) to regulate transcriptional activity.

Interferon-stimulated genes

(ISGs). The transcriptional activity of ISGs is regulated by interferon-induced Janus kinase–signal transducer and activator of transcription (JAK–STAT) signalling. ISGs can contain one or more interferon-stimulated response element (ISRE) and/or gamma-activated sequence element in their promoter regions. Some ISGs are also regulated by other transcription factors (such as nuclear factor-κB).

Dextran sodium sulfate-induced colitis

Dextran sodium sulfate can be provided in drinking water to chemically induce intestinal inflammation as a model for inflammatory bowel diseases in mice. This treatment disrupts the epithelial integrity in the colon and subsequently leads to dissemination of the luminal contents to the underlying tissue.

Blood–brain barrier

A selective, semipermeable barrier that separates the central nervous system from the circulating blood. It is formed by tight-junction connections of endothelial cells, astrocytic end-feet and pericytes.

HAP1 cells

A near-haploid cell line derived from the male chronic myelogenous leukaemia cell line KBM-7. Owing to their near-haploid karyotype, HAP1 cells are frequently used to generate CRISPR–Cas-mediated knockouts or to carry out genome-wide mutagenesis studies.

Tuft cells

Specialized epithelial cells located in various mucosal tissues that can detect allergens or parasitic pathogens through chemical-sensing (taste) receptors. They release IL-25 to promote immune cell infiltration, mucus production, muscle contraction and tissue repair.

Microfold cells

(M cells). Specialized epithelial cells located in mucosal tissues, such as the intestine or respiratory tract, that provide antigens from the exterior environment to macrophages or dendritic cells through transcytosis in order to initiate an immune response.

Ifnlr1 tm1b mice

A mouse strain that harbours a LacZ-tagged null allele under the control of the endogenous Ifnlr1 promoter. Tissue-specific expression of Ifnlr1 can be visualized by β-galactosidase staining.

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Ye, L., Schnepf, D. & Staeheli, P. Interferon-λ orchestrates innate and adaptive mucosal immune responses. Nat Rev Immunol 19, 614–625 (2019). https://doi.org/10.1038/s41577-019-0182-z

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