Functions of IFNλs in Anti-Bacterial Immunity at Mucosal Barriers

Abstract

Type III interferons (IFNs), or IFNλs, are cytokines produced in response to microbial ligands. They signal through the IFNλ receptor complex (IFNLR), which is located on epithelial cells and select immune cells at barrier sites. As well as being induced during bacterial or viral infection, type III IFNs are produced in response to the microbiota in the lung and intestinal epithelium where they cultivate a resting antiviral state. While the multiple anti-viral activities of IFNλs have been extensively studied, their roles in immunity against bacteria are only recently emerging. Type III IFNs increase epithelial barrier integrity and protect from infection in the intestine but were shown to increase susceptibility to bacterial superinfections in the respiratory tract. Therefore, the effects of IFNλ can be beneficial or detrimental to the host during bacterial infections, depending on timing and biological contexts. This duality will affect the potential benefits of IFNλs as therapeutic agents. In this review, we summarize the current knowledge on IFNλ induction and signaling, as well as their roles at different barrier sites in the context of anti-bacterial immunity.

Keywords: IFNλs; bacterial infection; epithelial barrier; interferon signaling; mucosal barrier; type III interferon.

Figure 1

Functions of IFNλ at barrier sites at steady state and during bacterial infection. At barrier sites, detection of Microbe-Associated Molecular Patterns (MAMPs) by Pattern Recognition Receptors (PRRs) triggers IFNλ production (in yellow) and subsequent expression of IFN-stimulated genes (ISGs). IFNλ can enhance (green lines) or inhibit (red lines) host immune responses. In infected or inflamed lungs (left panel), IFNλ and ISGs restrict neutrophil recruitment, resulting in increased bacterial burdens. IFNλ also decreases tight junction protein production, facilitating bacterial translocation and promoting bacterial superinfections. In contrast, IFNλ promotes the phagocytic activity of macrophages. During bacterial infections of the intestinal tract (lower right panel), IFNλ strengthens tight junction proteins, preventing bacterial transmigration. IFNλ also impairs neutrophil recruitment and reactive oxygen species (ROS) production to limit tissue destruction. At both sites (top right panel), steady-state detection of the bacterial microbiota induces the production of IFNλs, whose signaling drives homeostatic expression of ISGs. The resulting basal ISG response protects against viral infections.