Post-transcriptional regulatory feedback encodes JAK-STAT signal memory of interferon stimulation

Abstract

Immune cells fine tune their responses to infection and inflammatory cues. Here, using live-cell confocal microscopy and mathematical modelling, we investigate interferon induced JAK-STAT signalling in innate immune macrophages. We demonstrate that transient exposure to IFN-{gamma} stimulation induces a long-term desensitisation of STAT1 signalling and gene expression responses, revealing a dose- and time-dependent regulatory feedback that controls JAK-STAT responses upon re-exposure to stimulus. We show that IFN-/{beta}1 elicit different level of desensitisation from IFN-{gamma}, where cells refractory to IFN-/{beta}1 are sensitive to IFN-{gamma}, but not vice versa. We experimentally demonstrate that the underlying feedback mechanism involves regulation of STAT1 phosphorylation but is independent of new mRNA synthesis and cognate receptor expression. A new feedback model of the protein tyrosine phosphatase activity recapitulates experimental data and demonstrates JAK-STAT networks ability to decode relative changes of dose, timing, and type of temporal interferon stimulation. These findings reveal that STAT desensitisation renders cells with signalling memory of type I and II interferon stimulation, which in the future may improve administration of interferon therapy.