Nuclear factor of activated T cells regulates the expression of interleukin-4 in Th2 cells in an all-or-none fashion

J Biol Chem. 2014 Sep 26;289(39):26752-26761. doi: 10.1074/jbc.M114.587865. Epub 2014 Jul 17.

Abstract

Th2 memory lymphocytes have imprinted their Il4 genes epigenetically for expression in dependence of T cell receptor restimulation. However, in a given restimulation, not all Th cells with a memory for IL-4 expression express IL-4. Here, we show that in reactivated Th2 cells, the transcription factors NFATc2, NF-kB p65, c-Maf, p300, Brg1, STAT6, and GATA-3 assemble at the Il4 promoter in Th2 cells expressing IL-4 but not in Th2 cells not expressing it. NFATc2 is critical for assembly of this transcription factor complex. Because NFATc2 translocation into the nucleus occurs in an all-or-none fashion, dependent on complete dephosphorylation by calcineurin, NFATc2 controls the frequencies of cells reexpressing Il4, translates analog differences in T cell receptor stimulation into a digital decision for Il4 reexpression, and instructs all reexpressing cells to express the same amount of IL-4. This analog-to-digital conversion may be critical for the immune system to respond to low concentrations of antigens.

Keywords: Calcineurin; Cytokine; NFAT Transcription Factor; T-cell; T-cell Receptor (TCR).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / physiology
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / immunology
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Nucleus / genetics
  • Cell Nucleus / immunology
  • Cell Nucleus / metabolism*
  • DNA Helicases / genetics
  • DNA Helicases / immunology
  • DNA Helicases / metabolism
  • E1A-Associated p300 Protein / genetics
  • E1A-Associated p300 Protein / immunology
  • E1A-Associated p300 Protein / metabolism
  • GATA3 Transcription Factor / genetics
  • GATA3 Transcription Factor / immunology
  • GATA3 Transcription Factor / metabolism
  • Gene Expression Regulation / physiology*
  • Interleukin-4 / biosynthesis*
  • Interleukin-4 / genetics
  • Interleukin-4 / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • NFATC Transcription Factors / genetics
  • NFATC Transcription Factors / immunology
  • NFATC Transcription Factors / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / immunology
  • Nuclear Proteins / metabolism
  • Phosphorylation / physiology
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • Response Elements / physiology*
  • STAT6 Transcription Factor / genetics
  • STAT6 Transcription Factor / immunology
  • STAT6 Transcription Factor / metabolism
  • Th2 Cells / cytology
  • Th2 Cells / immunology
  • Th2 Cells / metabolism*
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / immunology
  • Transcription Factor RelA / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / immunology
  • Transcription Factors / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Cmip protein, mouse
  • GATA3 Transcription Factor
  • Gata3 protein, mouse
  • NFATC Transcription Factors
  • Nfatc2 protein, mouse
  • Nuclear Proteins
  • Receptors, Antigen, T-Cell
  • Rela protein, mouse
  • STAT6 Transcription Factor
  • Stat6 protein, mouse
  • Transcription Factor RelA
  • Transcription Factors
  • Interleukin-4
  • E1A-Associated p300 Protein
  • Ep300 protein, mouse
  • Smarca4 protein, mouse
  • DNA Helicases