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FOXP3 controls regulatory T cell function through cooperation with NFAT.

by Wu Y, Borde M, Heissmeyer V, Feuerer M, Lapan AD, Stroud JC, Bates DL, Guo L, Han A, Ziegler SF, Mathis D, Benoist C, Chen L, Rao A
Cell.

Article 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.

FATtening Our Understanding of FoxP3 (IJC: 10-05-2006)

By: Anonymous - Sat 10/28/2006 AM

The bottom line in this manuscirpt is that FoxP3 competes with the AP-1 (Fos/Jun)transcription factor for binding to NFAT resulting in upregulated Treg genes CD25 and CTLA4 and Treg function. Crystal structure analyses of FoxP2-NFAT complexes (see picture) suggested potential interaction domains that when disrupted in Foxp3 led to impaired FoxP3 downstream effects. I would have liked to see some biochemical demonstration of their interaction, other than one modestly convincing gel-shift, but I bought into the story. I can't really comment on the structural ribbon diagrams, but I suppose they were informative to those who know what to look for. The most convincing Figure was Figure 7 which really supported their hypothesis, especially after trying to figure out what was going on in Figure 5, which was dicey. I have one big criticism, the ChIP assays in Figure 6. Here they really should have performed ChIPs against AP-1 and demonstrated an inverse correlation between the presence of AP-1/NFAT and FoxP3/NFAT complexes on the genes they examined.

Source: http://immunologyjournalclub.blogspot.com/200...

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