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*
Celltech R&D, Inc., Bothell, WA 98021; and
Virginia Mason Research Center, Seattle, WA 98101.
In the absence of the recently identified putative transcription
factor scurfin, mice develop a lymphoproliferative disorder resulting
in death by 3 wk of age from a pathology that resembles TGF-
or
CTLA-4 knockout mice. In this report, we characterize mice that
overexpress the scurfin protein and demonstrate that these animals have
a dramatically depressed immune system. Mice transgenic for the
Foxp3 gene (which encodes the scurfin protein)
have fewer T cells than their littermate controls, and those T cells
that remain have poor proliferative and cytolytic responses and make
little IL-2 after stimulation through the TCR. Although thymic
development appears normal in these mice, peripheral lymphoid organs,
particularly lymph nodes, are relatively acellular. In a separate
transgenic line, forced expression of the gene specifically in the
thymus can alter thymic development; however, this does not appear to
affect peripheral T cells and is unable to prevent disease in mice
lacking a functional Foxp3 gene, indicating that the
scurfin protein acts on peripheral T cells. The data indicate a
critical role for the Foxp3 gene product in the function
of the immune system, with both the number and functionality of
peripheral T cells under the aegis of the scurfin
protein.
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