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FOXP3 controls regulatory T cell function through cooperation with NFAT.
- Source :
-
Cell [Cell] 2006 Jul 28; Vol. 126 (2), pp. 375-87. - Publication Year :
- 2006
-
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.
- Subjects :
- 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
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
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
Up-Regulation
Forkhead Transcription Factors metabolism
NFATC Transcription Factors metabolism
T-Lymphocytes, Regulatory immunology
Subjects
Details
- Language :
- English
- ISSN :
- 0092-8674
- Volume :
- 126
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cell
- Publication Type :
- Academic Journal
- Accession number :
- 16873067
- Full Text :
- https://doi.org/10.1016/j.cell.2006.05.042