Functional Differences in Type I versus Type III Interferon Mediated Immunity in Intestinal Epithelial Cells

Type I interferon (IFN) mediated innate immunity is ubiquitous. On the contrary, type III IFN signaling is confined to epithelial cells due to the restricted expression of its receptor. It is currently believed that both cytokines have fully redundant functions. However, the epithelium specificity of type III IFNs strongly suggests that both IFNs must have functional differences at epithelial surfaces.

Here, we use human intestinal epithelial cells (IECs) to study both the antiviral innate immune response and the functional differences of both IFNs at epithelial surfaces. We found that IECs, upon enteric virus infection, selectively secrete only type III IFNs, although both type I and III IFNs are transcriptionally upregulated. Interestingly, IECs can respond to both IFNs and pre-treatment of the cells with either IFN protects against viral infection. Biochemical analysis revealed differences in Jak/STAT signaling between both IFNs. Moreover, while transcript profiling revealed that both IFNs induced the same set of IFN stimulated genes (ISGs), Q-PCR analysis revealed that the kinetics of induction and regulation of a large set of ISGs and transcription factors differs depending on the IFNs. Type I IFN induces a strong stimulation of ISGs while type III IFNs signaling induces just enough ISGs to confer IECs an antiviral state.

In this work we define, for the first time, functional differences between type I and type III IFN signaling in epithelial cells and we propose that type III IFN signaling is specifically tailored to efficiently combat infection without inducing an excessive pro-inflammatory response.