Opposites Attach

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Science  28 Jul 2006:
Vol. 313, Issue 5786, pp. 413
DOI: 10.1126/science.313.5786.413b

Regulatory T cell activity depends on a course of gene expression and repression piloted by the Forkhead transcriptional factor FOXP3. Loss or impairment of FOXP3 disrupts the balancing of T cell responses and can lead to autoimmune disorders. The ability of FOXP3 to regulate the targets of the cytokine-activating transcription factor NFAT led Wu et al. to test whether the two factors cooperate directly. FOXP3 was found to complex with NFAT in a T cell line, resulting in the repressed activity of other complexes formed between NFAT and its cytokine-activating partner AP1, as well as in the enhanced binding of FOXP3 to its own DNA targets. The structure of a closely related factor, FOXP2, in a ternary complex with NFAT and DNA, was used to guide the introduction of mutations in FOXP3 that interfered with the interaction of NFAT and FOXP3; the levels of transcriptional repression of NFAT targets and activation of FOXP3-induced genes were thereby reduced. The inability of T cells carrying these mutations to control disease in a mouse model of autoimmune diabetes provides evidence that the formation of alternate transcriptional complexes by NFAT critically shapes the distinctive programs of effector and regulatory T cells. — SJS

Cell 126, 10.1016/j.cell.2006.05.042 (2006).

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