Type III interferons: Balancing tissue tolerance and resistance to pathogen invasion

Abstract

Type III IFNs, or IFN-λ, are the newest members of the IFN family and were long believed to play roles that were redundant with those of type I IFNs. However, IFN-λ displays unique traits that delineate them as primary protectors of barrier integrity at mucosal sites. This unique role stems both from the restricted expression of IFN-λ receptor, confined to epithelial cells and to a limited pool of immune cells, and from unique immunomodulatory properties of IFN-λ. Here, we discuss recent findings that establish the unique capacity of IFN-λ to act at the barriers of the host to balance tissue tolerance and immune resistance against viral and bacterial challenges.

Figure 1.

IFN-λ protects the airways against IAV infection. IFN-λ is produced in the upper airways in response to IAV infection and protect the nasal epithelium early after IAV encounter. In the lower airways, at early time points and low infection IAV titers, IFN-λ is sufficient to protect the host from IAV infection. IFN-λ directly induces ISGs in epithelial cells and neutrophils and prevents viral infection but do not induce proinflammatory cytokine production. IFN-λ stimulates long-lasting adaptive immunity by inducing TSLP secretion by airway M cells, which in turn stimulates CD103⁺ DCs to promote germinal center response. CD103⁺ DCs also respond directly to IFN-λ stimulation to promote CD8⁺ T-cell memory. At high viral titers, type I and type III IFNs are both needed for host protection. The production of type I IFNs is associated with a stronger inflammatory response and with the secretion of proinflammatory cytokines. GC B cells, germinal center B cells; Tfh, T follicular helper cell. Images were created with BioRender.

Figure 2.

IFN-λ protects intestinal barrier functions. In homeostatic conditions, commensal viruses stimulate basal IFN-λ production that maintains both an antiviral state and an anti-inflammatory environment. Basal ISGs induced by IFN-λ in IECs protect them from enteric viral infections. During enteric viral infections, IFN-λ is preferentially induced and protects the mucosae from epithelial tropic viruses such as rotavirus, reovirus, and persistent strains of norovirus. Low transcript expression of IFNAR1/2 by IECs renders them largely dependent on IFN-λ for protection against viruses. In contrast, protection against viruses that can bypass the epithelium and infect lymphocytes residing in the lamina propria, such as reovirus and acute strains of norovirus, is dependent on type I IFNs. During acute intestinal inflammation, IFN-λ induced by commensals inhibits neutrophil-damaging functions and protects the mucosal barrier from excessive damage. Images were created with BioRender.