Interferon lambda 4 is a gut antimicrobial protein.

To withstand complex microbial challenges, the mammalian gut largely depends on the secretion of diverse antimicrobial proteins. Type III interferons (IFNλs) are ordinarily considered inducible antiviral cytokines involved in intestinal immunity. Unlike other IFNλs, we found that newly identified IFNλ4 is an intestinal antibacterial protein. Large amounts of natural IFNλ4 are present in the secretory layer of the intestinal tracts of healthy piglets, which suggests that IFNλ4 is in direct physiological contact with microbial pathogens. We also identified two biochemical functions of mammalian IFNλ4, the induction of bacterial agglutination and direct microbial killing, which are not functions of the other IFNλs. Further mechanistic investigations revealed that after binding to the carbohydrate fraction of lipopolysaccharide, mammalian IFNλ4 self-assembles into bacteria-surrounding nanoparticles that agglutinate bacteria, and that its unique cationic amphiphilic molecular structure facilitates the destruction of bacterial membranes. Our data reveal features of IFNλ4 distinct from those of previously reported IFNλs and suggest that noncanonical IFNλ4 is deeply involved in intestinal immunity, beyond simply cytokine signaling.