Editors' ChoiceImmunology

Both an Activator and a Repressor

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Science's STKE  01 Aug 2006:
Vol. 2006, Issue 346, pp. tw256
DOI: 10.1126/stke.3462006tw256

The transcription factor NFAT is a regulator of two opposing T cell responses: anergy and activation. Wu et al. provide evidence that production of regulatory T cells also involves NFAT through the formation of a complex with FOXP3, another transcription factor that is known as a regulatory T cell specification factor. Reporter gene assays with the ARRE2 element of the gene encoding interleukin 2 (IL-2) indicated that FOXP3 inhibited transcription mediated by NFAT:AP-1 complexes. FOXP1, FOXP2, and FOXP3 all bound poorly to the ARRE2 element unless the NFAT DNA binding domain was also included in the reaction, suggesting that NFAT and FOXP transcription factors form a cooperative DNA binding complex. The crystal structure of the NFAT Rel homology region (RHR, the DNA binding region) and the FOXP2 forkhead domain bound to double-stranded DNA with the ARRE2 site showed that NFAT and FOXP2 formed a complex, with NFAT binding to the 5′ portion of the promoter and FOXP2 binding to a low-affinity site in the 3′ portion of the promoter. Comparison of this structure with that of NFAT:Fos:Jun:DNA shows that the DNA adopted different shapes to maximize the interactions with each different transcription factor complex and that the binding of NFAT was very similar in each structure. Expression of FOXP3 mutants that disrupted its interaction with NFAT exhibited decreased ability of coexpressed wild-type FOXP3 to inhibit IL-2 production in murine primary T cells. The Ctla4 gene is stimulated by expression of FOXP3, and the promoter contains a consensus binding site for NFAT:AP-1 or NFAT:FOXP3. The FOXP3 interaction mutants prevented the increase in cell surface CTLA4 and CD25 stimulated by coexpressed wild-type FOXP3. Thus, the NFAT:FOXP3 complex can serve as a repressor or activator, depending on the target gene. In a mouse model of autoimmune diabetes, cotransfer of T cells expressing wild-type FOXP3, but not the interaction mutants, with the Th1 cells that trigger the diabetes prevented the onset of diabetes in the mice. Thus, FOXP3 does appear to contribute to the regulatory T cell phenotype through the formation of the NFAT:FOXP3 complex.

Y. Wu, M. Borde, V. Heissmeyer, M. Feuerer, A. D. Lapan, J. C. Stroud, D. L. Bates, L. Guo, A. Han, S. F. Ziegler, D. Mathis, C. Benoist, L. Chen, A. Rao, FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 126, 375-387 (2006). [Online Journal]

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