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Isoform-Specific Inhibition of ROR-Mediated Transcriptional Activation by Human FOXP3¹

Jianguang Du^2,*, Chunjian Huang^*, Baohua Zhou^* and Steven F. Ziegler^3,*,

^* Immunology Program, Benaroya Research Institute, Seattle, WA 98101; and Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195

FOXP3 is a forkhead family transcriptional repressor important for the development and function of CD4⁺CD25⁺ regulatory T cells. In humans, FOXP3 is expressed as two isoforms, a full-length form and a smaller form lacking exon 2. These two isoforms are expressed in approximately equal amounts in circulating regulatory T cells, and are induced equally in freshly activated CD4⁺CD25^– T cells. Herein, we show that FOXP3 interacts with retinoic acid receptor-related orphan receptor (ROR), and that this interaction inhibits transcriptional activation mediated by ROR. Full-length FOXP3, but not the isoform lacking exon 2, interacts with ROR, and the region of FOXP3 involved in the interaction is encoded by exon 2. Mutation of the LxxLL motif in FOXP3, located in exon 2, abolished interaction and repression by FOXP3. Additionally, the inhibition of ROR by FOXP3 does not require an intact forkhead domain, demonstrating a mode of FOXP3 function that is independent of DNA binding. Interestingly, expression of ROR in T cells leads to the expression of genes that define Th17 cells, and the expression of each of these gene was inhibited by coexpression of full-length, but not Ex2, FOXP3. These data expand the possible targets of FOXP3-mediated repression and demonstrate functional differences between FOXP3 isoforms.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by National Institutes of Health Grant AI48779 and the Juvenile Diabetes Research Foundation International Collaborative Center for Cellular Therapy (to S.F.Z.).

² Current address: Department of Biochemistry and Cell Biology, State University of New York, Stony Brook, NY 11794.

³ Address correspondence and reprint requests to Dr. Steven F. Ziegler, Benaroya Research Institute at Virginia Mason, 1201 9th Avenue, Seattle, WA 98101. E-mail address: sziegler{at}benaroyaresearch.org

⁴ Abbreviations used in this paper: Treg, regulatory T; AF2, activation function 2; FKH, forkhead; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome; qPCR, quantitative PCR; ROR, retinoic acid receptor-like orphan receptor; RORE, ROR response element.

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The JI 2008 180: 4349-4350. [Full Text]