Structure of a domain-swapped FOXP3 dimer on DNA and its function in regulatory T cells

Immunity. 2011 Apr 22;34(4):479-91. doi: 10.1016/j.immuni.2011.02.017. Epub 2011 Mar 31.

Abstract

The transcription factor FOXP3 is essential for the suppressive function of regulatory T cells that are required for maintaining self-tolerance. We have solved the crystal structure of the FOXP3 forkhead domain as a ternary complex with the DNA-binding domain of the transcription factor NFAT1 and a DNA oligonucleotide from the interleukin-2 promoter. A striking feature of this structure is that FOXP3 forms a domain-swapped dimer that bridges two molecules of DNA. Structure-guided or autoimmune disease (IPEX)-associated mutations in the domain-swap interface diminished dimer formation by the FOXP3 forkhead domain without compromising FOXP3 DNA binding. These mutations also eliminated T cell-suppressive activity conferred by FOXP3, both in vitro and in a murine model of autoimmune diabetes in vivo. We conclude that FOXP3-mediated suppressor function requires dimerization through the forkhead domain and that mutations in the dimer interface can lead to the systemic autoimmunity observed in IPEX patients.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Forkhead Transcription Factors / chemistry*
  • Forkhead Transcription Factors / immunology*
  • Humans
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • NFATC Transcription Factors / chemistry
  • NFATC Transcription Factors / immunology
  • Protein Multimerization
  • Protein Structure, Quaternary
  • Protein Structure, Tertiary
  • Sequence Alignment
  • T-Lymphocytes, Regulatory / chemistry*
  • T-Lymphocytes, Regulatory / immunology*

Substances

  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • NFATC Transcription Factors