The Scurfy mutation of FoxP3 in the thymus stroma leads to defective thymopoiesis.
The Scurfy mutation of the FoxP3 gene (FoxP3(sf)) in the mouse and analogous mutations in human result in lethal autoimmunity. The mutation of FoxP3 in the hematopoietic cells impairs the development of regulatory T cells. In addition, development of the Scurfy disease also may require mutation of the gene in nonhematopoietic cells. The T cell-extrinsic function of FoxP3 has not been characterized. Here we show that the FoxP3(sf) mutation leads to defective thymopoiesis, which is caused by inactivation of FoxP3 in the thymic stromal cells. FoxP3 mutation also results in overexpression of ErbB2 in the thymic stroma, which may be involved in defective thymopoiesis. Our data reveal a novel T cell-extrinsic function of FoxP3. In combination, the T cell-intrinsic and -extrinsic defects provide plausible explanation for the severity of the autoimmune diseases in the scurfy mice and in patients who have immunodysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome.
Chang
Xing
X
Division of Cancer Immunology, Department of Pathology and Comprehensive Cancer Center, Ohio State University Medical Center, Columbus, OH 43210, USA.
Gao
Jian Xin
JX
Jiang
Qi
Q
Wen
Jing
J
Seifers
Nick
N
Su
Lishan
L
Godfrey
Virginia L
VL
Zuo
Tao
T
Zheng
Pan
P
Liu
Yang
Y
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001327:Autoimmune Diseases / Q000235:genetics* / Q000473:pathology; D001973:Bromodeoxyuridine; D017931:DNA Primers; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics*; D008156:Luciferases; D008206:Lymphatic Diseases / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology*
D017931:DNA Primers; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D008156:Luciferases; D001973:Bromodeoxyuridine