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* Benaroya Research Institute, Virginia Mason, Seattle, WA 98101;
Department of Immunology, and
Department of Pediatrics, University of Washington, Seattle, WA 98195; and
Children’s Hospital & Regional Medical Center, University of Washington, Seattle, WA 98109
Foxp3 has been shown to be both necessary and sufficient for the development and function of naturally arising CD4+CD25+ regulatory T cells in mice. Mutation of Foxp3 in Scurfy mice and FOXP3 in humans with IPEX results in fatal, early onset autoimmune disease and demonstrates the critical role of FOXP3 in maintaining immune homeostasis. The FOXP3 protein encodes several functional domains, including a C2H2 zinc finger, a leucine zipper, and a winged-helix/forkhead (FKH) domain. We have shown previously that FOXP3 functions as a transcriptional repressor and inhibits activation-induced IL-2 gene transcription. To characterize the role of each predicted functional domain on the in vivo activity of FOXP3, we have evaluated the location of point mutations identified in a large cohort of patients with the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) and found them to cluster primarily within the FKH domain and the leucine zipper, but also present within the poorly defined N-terminal portion of the protein. The molecular functions of each of the IPEX-targeted domains were investigated. We show that FOXP3 is constitutively localized to the nucleus and this localization requires sequences at both the amino and C-terminal ends of its FKH domain. Moreover, FOXP3 was found to homodimerize through its leucine zipper. We also identify a novel functional domain within the N-terminal half of FOXP3, which is required for FOXP3-mediated repression of transcription from both a constitutively active and a NF-AT-inducible promoter. Furthermore, we demonstrate that IPEX mutations in these domains correlate with deficiencies in FOXP3 repressor function, corroborating their in vivo relevance.
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 J.E.L. is supported by a Cancer Research Institute training grant. T.R.T. is supported by a Pfizer postdoctoral fellowship and Child Health Research Center Grant HD043376-03. H.D.O. is supported by National Institutes of Health Grant HD17427 and grants from the Immunodeficiency Foundation and the Jeffrey Modell Foundation. S.F.Z. is supported by National Institutes of Health Grant AI48779 and grants from the American Diabetes Association and the Juvenile Diabetes Research Foundation.
2 J.E.L. and T.R.T. contributed equally to this work.
3 Current address: Macrogenics, 1441 North 34th Street, Seattle, WA 98103.
4 Address correspondence and reprint requests to Dr. Steven F. Ziegler, Benaroya Research Institute, 1201 Ninth Avenue, Seattle, WA 98101. E-mail address: sziegler{at}benaroyaresearch.org
5 Abbreviations used in this paper: FKH, forkhead; CtBP1, C-terminal binding protein 1; DBD, DNA binding domain; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome; NLS, nuclear localization signal; Treg, regulatory T cell; wt, wild type.
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