Interferon-λ and Interleukin 22 Act Synergistically for the Induction of Interferon-Stimulated Genes and Control of Rotavirus Infection

Pedro P Hernández, Tanel Mahlakõiv, Ines Yang, Vera Schwierzeck, Nam Nguye,
Fabian Guendel, Konrad Gronke, Bernhard Ryffel, Christoph Hölscher, Laure Dumoutier, Jean-Christophe Renauld, Sebastian Suerbaum, Peter Staeheli & Andreas Diefenbach

Nat Immunol. 2015 Jul;16(7):698-707. doi: 10.1038/ni.3180. Epub 2015 May 25.

HERNANDEZ_photo

Pedro P Hernández

Tanel

Tanel Mahlakõiv

Peter

Peter Staeheli

Immunologe Andreas Diefenbach

Andreas Diefenbach

 

 

 

 

 

Emerging evidence supports the view that immunity against many viruses that replicate in epithelial cells at barrier surfaces is orchestrated by interferon (IFN)-λ, a mucosal type III IFN distinct from the various type I IFNs (IFN-I). This is best documented for rotavirus infection, the leading cause of viral gastroenteritis in infants and which causes more than 500,000 fatalities worldwide, annually. IFN-λ is closely related to IL-22, a cytokine abundantly produced by innate lymphoid cells at mucosal surfaces where it induces the expression antibacterial factors and of genes that promote tissue repair. Interestingly, the gene encoding the α-chain of the IL-22 receptor (Il22ra1) is the closest relative of the gene encoding the IFN-λR1 chain (Ifnlr1), both of which are members of the extended IL-10 receptor family. The Il22ra1 and Ifnlr1 genes are adjacent in the mouse and in the human genomes, and both IL-22Rα and IFN-λR1 associate with the IL-10Rβ chain (IL-10R2) to form heterodimeric receptor complexes. Importantly IFN-λR and IL-22R are both preferentially expressed by epithelial cells, which indicates important roles in controlling epithelial function. While both type I and type III interferons induce the expression of interferon stimulated genes (ISGs) through STAT1 and STAT2 signaling, all of the known biological functions of IL-22 have been linked to STAT3 signaling pathway. Given the close relationship between IL-22 and IFN-λ, we investigated the role of IL-22 in protection against rotavirus, which has preferential tropism to epithelial cells of the small intestine. We found that group 3 innate lymphoid cell (ILC3)–derived IL-22 was required for control of infection with murine rotavirus. IL-1α, an epithelial alarmin released by virus-infected cells, but not IL-23 or IL-1β, mediated high expression of IL-22 by ILC3 cells upon rotavirus infection. IL-22-mediated protection against rotavirus-mediated tissue damage did not require STAT3. IL-22 acted in synergy with IFN-λ for optimal activation of STAT1 and expression of ISGs. Our data contribute to understanding immunity in early life when adaptive immune system components are not fully operative yet and identify a mechanism of cooperation that could be exploited for the design of therapies against viruses able to dampen antiviral defense. PubMed:26006013