IFN-lambda Receptor

The interferon-lambda receptor (IFN-λR) is the cell-type-restricted receptor complex mediating type III interferon signaling, composed of the private IFNLR1 (also called IL-28Rα) chain and the shared IL10RB (IL-10Rβ) chain. IFNLR1, a class II cytokine receptor with two extracellular fibronectin type III domains, determines the remarkably confined expression pattern of the receptor: epithelial cells of the respiratory, gastrointestinal and urogenital tracts, hepatocytes, and selected neuronal populations, with minimal expression on leukocytes except neutrophils and pDCs. This distribution contrasts sharply with the ubiquitous IFNAR and allows IFN-λ to mount potent antiviral defense precisely at mucosal barriers while sparing the systemic hematologic toxicity of type I interferons. Ligand binding activates JAK1 (on IFNLR1) and TYK2 (on IL10RB), assembling STAT1-STAT2-IRF9 (ISGF3) to induce ISGs. Human IFNLR1 variation, including the rs12854436 haplotype and loss-of-function alleles, shapes outcomes of hepatitis C, influenza, SARS-CoV-2 and enterovirus infections.