Biphasic RLR-IFN-ß 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/ß. However, not every infected cell produces IFN-α/ß that exhibits cellular heterogeneity in antiviral immune responses. Using the IFN-ß-GFP reporter system, we observed bimodal IFN-ß 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-ß expression. Bimodal IFN-ß production with intracellular dsRNA was disturbed by blockage of IFN-α/ß secretion or by silencing of the IFN-α/ß receptor. Amplification of RLRs was critical in the generation of bimodality of IFN-ß production, because IFN-ß(high) population expressed more RLRs than IFN-ß(low) population. In addition, bimodality in IFN-ß production results in biphasic cellular response against infection, because IFN-ß(high) population was more prone to apoptosis than IFN-ß(low) population. These results suggest that RLR-mediated biphasic cellular response may act to restrict the number of cells expressing IFN-ß and undergoing apoptosis in the infected population.