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Binding of interferons (IFN) to their respective surface receptors activates JAK kinases such as JAK1, JAK2 and TYK2. Upon activation these kinases mediate the phosphorylation of STAT molecules, which eventually promotes the expression of a large number of IFN-stimulated genes (ISGs) encoding antiviral resistance factors. TYK2 is associated with both the IFNAR1 and the IL-10Rβ receptor chain, each forming a subunit of either the type I or type III IFN receptor complex.
Here we aimed to clarify the role of TYK2 in the signaling pathways of type I (IFN-α/β) and type III IFNs (IFN-λ) using primary airway epithelial cells and primary mini-gut organoids derived from mice harboring defective or functional alleles for Tyk2.
Both primary culture systems readily responded to IFN-λ by upregulating ISG expression irrespective of whether they carried functional or defective Tyk2 alleles. In contrast, IFN-α mediated ISG induction was severely diminished in cells with no functional TYK2. When mice were treated with IFN-α or IFN-λ before intranasal infection with a lethal dose of influenza A virus, IFN-λ efficiently protected from disease irrespective of whether the mice carried functional or defective Tyk2 alleles. In contrast, IFN-α was only protective in animals carrying a functional Tyk2 gene, while Tyk2-deficient animals succumbed to the infection.
We conclude that Tyk2 deficiency severely limits IFN-α signaling but does not affect IFN-λ mediated ISG induction in respiratory and intestinal epithelial cells or protection against a lethal infection of the respiratory tract.
| Choose primary session | Innate Immunity |
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