FOXP3 controls regulatory T cell function through cooperation with NFAT.
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.
Wu
Yongqing
Y
Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, CO 80309, USA.
Borde
Madhuri
M
Heissmeyer
Vigo
V
Feuerer
Markus
M
Lapan
Ariya D
AD
Stroud
James C
JC
Bates
Darren L
DL
Guo
Liang
L
Han
Aidong
A
Ziegler
Steven F
SF
Mathis
Diane
D
Benoist
Christophe
C
Chen
Lin
L
Rao
Anjana
A
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D019281:Dimerization; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D015854:Up-Regulation
D015415:Biomarkers; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins; D012097:Repressor Proteins; D008156:Luciferases