Pharmacological inhibition of tyrosine kinase 2 preserves interferon-?-mediated protection (neutrophils)

Treating inflammatory diseases with Janus kinase 1/2 (JAK1/2) inhibitors bears the risk that patients acquire viral infections due to unwanted immune suppression. Tyrosine kinase 2 (TYK2), a JAK family member, is required for type I interferon (IFN-a/ß) signaling, but its role in type III IFN (IFN-?) signaling is still under debate. We found that the selective TYK2 inhibitor BMS-986165 blocked potentially noxious type I IFN signaling without altering IFN-?-mediated gene expression. We show that epithelial cells do not require TYK2 for IFN-?-mediated signaling or antiviral protection. Lack of TYK2 diminished IFN-a-induced protection against lethal influenza virus infection of mice, but did not impair IFN-?-mediated antiviral protection. Our findings suggest that selective TYK2 inhibitors likely represent a superior treatment option for type I interferonopathies than broadly acting JAK1/2 inhibitors, as selective TYK2 inhibitors may counteract inflammatory responses without abolishing the beneficial antiviral effects of IFN-?. Overall design: WT or TYK2 KO neutropihls were mock treated or treated with either IFNab (0.3ng/ml) or IFNL (0.3/ml). Biological triplicates were run for every treatment group.