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
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Amino Acid Substitution
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Animals
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Binding Sites
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Biomarkers / metabolism
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Cells, Cultured
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Crystallography, X-Ray
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Dimerization
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Forkhead Transcription Factors / chemistry
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism*
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Genes, Reporter
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Humans
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Interleukin-2 / genetics
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Interleukin-2 / metabolism
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Jurkat Cells
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Luciferases / metabolism
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Mice
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Mice, Inbred NOD
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Models, Molecular
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Molecular Sequence Data
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NFATC Transcription Factors / chemistry
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NFATC Transcription Factors / genetics
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NFATC Transcription Factors / metabolism*
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Protein Binding
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Protein Structure, Tertiary
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Receptors, Interleukin-2 / genetics
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Receptors, Interleukin-2 / metabolism
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Retroviridae / genetics
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Sequence Homology, Amino Acid
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T-Lymphocytes, Regulatory / immunology*
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Up-Regulation
Substances
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Biomarkers
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FOXP3 protein, human
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Interleukin-2
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NFATC Transcription Factors
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Receptors, Interleukin-2
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Recombinant Proteins
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Repressor Proteins
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Luciferases