It is currently believed that both type I and III interferon (IFNs) have fully redundant functions. However, the preferential distribution of type III IFN receptor on epithelial cells strongly suggests functional differences at epithelial surfaces. We used mini-gut organoids to define the functions of both IFNs to protect the human gut against viral infection. We show that primary non-transformed human intestinal epithelial cells (hIECs) produce and secrete only type III IFN upon viral challenge. Interestingly, if provided in trans, hIECs respond to both IFNs by producing IFN stimulated genes (ISGs) that in turn induce an antiviral state. Using CRISPR-Cas9 mediated genetic ablation of IFN receptors, we show that either IFNs can independently restrict virus infection in hIECs. Importantly, we report differences in the mechanisms by which each IFN establishes the antiviral state. Contrary to type I IFN, the antiviral activity induced by type III IFN is strongly dependent on the mitogen-activated protein kinases (MAPK) signaling pathway, suggesting a pathway used by type III IFNs that non-redundantly contributes to the antiviral state. Moreover, while transcript profiling revealed that both IFNs induced the same set of ISGs, the kinetics of ISGs and transcription factors expression strictly depends on the IFNs. Type I IFN induces an acute strong stimulation of ISGs while type III IFNs signaling induces a delayed and reduced ISG expression to confer IECs an antiviral state. We demonstrate that these differences are due to the limited expression level of type II IFN receptors at the surface of hIECs
We propose that the human gastro-intestinal tract, has evolved to favor type III IFN-mediated response to pathogen infections as it allows for spatial segregation of signaling and moderate production of inflammatory signals which we suggest are key to maintain gut homeostasis.