IFNLR1

Interleukin-28 receptor alpha 1 (IFNLR1, also IL28RA or IL-28Rα) is the private ligand-binding subunit of the type III interferon receptor, forming the functional complex with IL10RB to receive IFN-λ1 (IL-29), IFN-λ2 (IL-28A), IFN-λ3 (IL-28B) and IFN-λ4. The mature protein is a 500-amino-acid type I transmembrane glycoprotein of the class II cytokine receptor family, featuring two fibronectin type III extracellular domains and a cytoplasmic tail with box 1 and tyrosine motifs recruiting JAK1 and STAT2. IFNLR1 expression is the gatekeeper of IFN-λ biology: it is concentrated on epithelial cells of airway, gut and reproductive tract, hepatocytes and certain neurons, endowing type III interferons with mucosal specificity and hematologic safety relative to type I IFNs. Genetic studies have exposed IFNLR1 as a prominent susceptibility gene-its variants modulate clearance of hepatitis C virus, severity of influenza, SARS-CoV-2 and respiratory syncytial virus disease, asthma exacerbation and norovirus susceptibility. Therapeutically, inhaled IFN-λ acting through IFNLR1 is in development for respiratory viral infection.