Biphasic RLR-IFN-β response controls the balance between antiviral immunity and cell damage

In RNA virus-infected cells, retinoic acid-inducible gene-I-like receptors (RLRs) sense foreign RNAs and activate signaling cascades to produce IFN-α/β. However, not every infected cell produces IFN-α/β that exhibits cellular heterogeneity in antiviral immune responses. Using the IFN-β-GFP reporter system, we observed bimodal IFN-β production in the uniformly stimulated cell population with intracellular dsRNA. Mathematical simulation proposed the strength of autocrine loop via RLR as one of the contributing factor for biphasic IFN-β expression. Bimodal IFN-β production with intracellular dsRNA was disturbed by blockage of IFN-α/β secretion or by silencing of the IFN-α/β receptor. Amplification of RLRs was critical in the generation of bimodality of IFN-β production, because IFN-β(high) population expressed more RLRs than IFN-β(low) population. In addition, bimodality in IFN-β production results in biphasic cellular response against infection, because IFN-β(high) population was more prone to apoptosis than IFN-β(low) population. These results suggest that RLR-mediated biphasic cellular response may act to restrict the number of cells expressing IFN-β and undergoing apoptosis in the infected population.