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J. Biol. Chem., Vol. 276, Issue 40, 37672-37679, October 5, 2001
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From the We have recently identified and cloned
Foxp3, the gene defective in mice with the
scurfy mutation. The immune dysregulation documented in
these mice and in humans with mutations in the orthologous gene
indicates that the foxp3 gene product, scurfin, is involved in the regulation of T cell activation and differentiation. The autoimmune state observed in these patients with the immune
dysregulation polyendocrinopathy, enteropathy, X-linked syndrome, or
X-linked autoimmunity-allergic dysregulation syndrome also points to a critical role for scurfin in the regulation of T cell homeostasis. FOXP3 encodes a novel member of the forkhead family of
transcription factors. Here we demonstrate that this structural domain
is required for nuclear localization and DNA binding. Scurfin,
transiently expressed in heterologous cells, represses transcription of
a reporter containing a multimeric forkhead binding site. Upon
overexpression in CD4 T cells, scurfin attenuates activation-induced
cytokine production and proliferation. We have identified FKH binding
sequences adjacent to critical NFAT regulatory sites in the promoters
of several cytokine genes whose expression is sensitive to changes in
SFN abundance. Our findings indicate that the ability of scurfin to
bind DNA, and presumably repress transcription, plays a paramount role
in determining the amplitude of the response of CD4 T cells to activation.
Scurfin (FOXP3) Acts as a Repressor of Transcription
and Regulates T Cell Activation*
,
Immunology Program, Virginia Mason
Research Center, Seattle, Washington 98101 and
§ Celltech-Chiroscience R&D, Bothell, Washington 98021
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of
Immunology, Virginia Mason Research Center, 1201 9th Ave., Seattle, WA 98101. Tel.: 206-344-7950; Fax: 206-223-7456; E-mail:
sziegler@vmresearch.org.
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