IFN-β Selectively Inhibits IL-2 Production through CREM-Mediated Chromatin Remodeling

J Immunol. 2015 Jun 1;194(11):5120-8. doi: 10.4049/jimmunol.1403181. Epub 2015 Apr 17.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arenaviridae Infections / immunology
  • Cells, Cultured
  • Chromatin Assembly and Disassembly / drug effects*
  • Cyclic AMP Response Element Modulator / genetics
  • Cyclic AMP Response Element Modulator / metabolism*
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases / genetics
  • Histones / genetics
  • Humans
  • Interferon-beta / pharmacology*
  • Interleukin-2 / antagonists & inhibitors*
  • Interleukin-2 / biosynthesis
  • Lymphocyte Activation / immunology
  • Lymphocytic choriomeningitis virus / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiple Sclerosis / immunology
  • Promoter Regions, Genetic / genetics
  • RNA Interference
  • RNA, Small Interfering
  • Receptor, Interferon alpha-beta
  • Receptors, Antigen, T-Cell / immunology
  • T-Lymphocytes, Regulatory / immunology*

Substances

  • Crem protein, mouse
  • Histone Deacetylase Inhibitors
  • Histones
  • Interleukin-2
  • RNA, Small Interfering
  • Receptors, Antigen, T-Cell
  • Cyclic AMP Response Element Modulator
  • Receptor, Interferon alpha-beta
  • Interferon-beta
  • Histone Deacetylases