IFN-β selectively inhibits IL-2 production through CREM-mediated chromatin remodeling

Dennis C. Otero, Nancy J. Fares-Frederickson, Menghong Xiao, Darren P. Baker, Michael David

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

IFN-β is widely used in the treatment of multiple sclerosis, yet the mechanism facilitating its efficacy remains unclear. IL-2 production by activated T cells, including those mediating autoimmunity, and subsequent autocrine stimulation is vital for T cell expansion and function. In this study, we demonstrate that in mouse and human T cells, IFN-β specifically inhibits the production of IL-2 upon TCR engagement without affecting other cytokines or activation markers. Rather than disrupting TCR signaling, IFN-β alters histone modifications in the IL-2 promoter to retain the locus in an inaccessible configuration. This in turn is mediated through the upregulation of the transcriptional suppressor CREM by IFN-β and consequent recruitment of histone deacetylases to the IL-2 promoter. In accordance, ablation of CREM expression or inhibition of histone deacetylases activity eliminates the suppressive effects of IFN-β on IL-2 production. Collectively, these findings provide a molecular basis by which IFN-β limits T cell responses.

Original languageEnglish (US)
Pages (from-to)5120-5128
Number of pages9
JournalJournal of Immunology
Volume194
Issue number11
DOIs
StatePublished - Jun 1 2015

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    Otero, D. C., Fares-Frederickson, N. J., Xiao, M., Baker, D. P., & David, M. (2015). IFN-β selectively inhibits IL-2 production through CREM-mediated chromatin remodeling. Journal of Immunology, 194(11), 5120-5128. https://doi.org/10.4049/jimmunol.1403181