FOXP3 controls regulatory T cell function through cooperation with NFAT

Cell. 2006 Jul 28;126(2):375-87. doi: 10.1016/j.cell.2006.05.042.

Abstract

Antigen stimulation of immune cells activates the transcription factor NFAT, a key regulator of T cell activation and anergy. NFAT forms cooperative complexes with the AP-1 family of transcription factors and regulates T cell activation-associated genes. Here we show that regulatory T cell (Treg) function is mediated by an analogous cooperative complex of NFAT with the forkhead transcription factor FOXP3, a lineage specification factor for Tregs. The crystal structure of an NFAT:FOXP2:DNA complex reveals an extensive protein-protein interaction interface between NFAT and FOXP2. Structure-guided mutations of FOXP3, predicted to progressively disrupt its interaction with NFAT, interfere in a graded manner with the ability of FOXP3 to repress expression of the cytokine IL2, upregulate expression of the Treg markers CTLA4 and CD25, and confer suppressor function in a murine model of autoimmune diabetes. Thus by switching transcriptional partners, NFAT converts the acute T cell activation program into the suppressor program of Tregs.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Binding Sites
  • Biomarkers / metabolism
  • Cells, Cultured
  • Crystallography, X-Ray
  • Dimerization
  • Forkhead Transcription Factors / chemistry
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Genes, Reporter
  • Humans
  • Interleukin-2 / genetics
  • Interleukin-2 / metabolism
  • Jurkat Cells
  • Luciferases / metabolism
  • Mice
  • Mice, Inbred NOD
  • Models, Molecular
  • Molecular Sequence Data
  • NFATC Transcription Factors / chemistry
  • NFATC Transcription Factors / genetics
  • NFATC Transcription Factors / metabolism*
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, Interleukin-2 / genetics
  • Receptors, Interleukin-2 / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Retroviridae / genetics
  • Sequence Homology, Amino Acid
  • T-Lymphocytes, Regulatory / immunology*
  • Up-Regulation

Substances

  • Biomarkers
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-2
  • NFATC Transcription Factors
  • Receptors, Interleukin-2
  • Recombinant Proteins
  • Repressor Proteins
  • Luciferases