title: IFN-β Selectively Inhibits IL-2 Production through CREM-Mediated Chromatin Remodeling.
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.
authors.affiliation: Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093;
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Otero
authors.affiliation: Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093;
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Fares-Frederickson
authors.affiliation: Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093;
authors.forename: Menghong
authors.initials: M
authors.lastname: Xiao
authors.affiliation: Biogen Idec, Cambridge, MA 02142; and.
authors.forename: Darren P
authors.initials: DP
authors.lastname: Baker
authors.affiliation: Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093; UC San Diego Moores Cancer Center, University of California San Diego, La Jolla, CA 92093 midavid@ucsd.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: David
mesh_terms: D000818:Animals; D001117:Arenaviridae Infections / Q000276:immunology; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects*; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics; D006657:Histones / Q000235:genetics; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D053633:Receptor, Interferon alpha-beta; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C497411:Crem protein, mouse; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D007376:Interleukin-2; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D051786:Cyclic AMP Response Element Modulator; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta; D006655:Histone Deacetylases