Biphasic RLR-IFN-beta Response Controls the Balance between Antiviral Immunity and Cell Damage

Abstract

In RNA virus-infected cells, retinoic acid-inducible gene-I-like receptors (RLRs) sense foreign RNAs and activate signaling cascades to produce IFN-alpha/beta. However, not every infected cell produces IFN-alpha/beta that exhibits cellular heterogeneity in antiviral immune responses. Using the IFN-beta-GFP reporter system, we observed bimodal IFN-beta 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-beta expression. Bimodal IFN-beta production with intracellular dsRNA was disturbed by blockage of IFN-alpha/beta secretion or by silencing of the IFN-alpha/beta receptor. Amplification of RLRs was critical in the generation of bimodality of IFN-beta production, because IFN-beta(high) population expressed more RLRs than IFN-beta(low) population. In addition, bimodality in IFN-beta production results in biphasic cellular response against infection, because IFN-beta(high) population was more prone to apoptosis than IFN-beta(low) population. These results suggest that RLR-mediated biphasic cellular response may act to restrict the number of cells expressing IFN-beta and undergoing apoptosis in the infected population. The Journal of Immunology, 2013, 190: 1192-1200.