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

Eirini Kalliara, Malgorzata Kardyńska, James Bagnall, David G. Spiller, Werner Muller, Dominik Ruckerl, Subhra K Biswas, Jarosław Śmieja, Pawel Paszek

Research output: Contribution to journalArticlepeer-review

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-γ 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-α/β1 elicit different level of desensitisation from IFN-γ, where cells refractory to IFN-α/β1 are sensitive to IFN-γ, 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 network’s 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.
Original languageEnglish
Article number947213
JournalFrontiers in Immunology
Volume13
Issue number947213
DOIs
Publication statusPublished - 27 Sep 2022

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  • Lydia Becker Institute

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