title: The Scurfy mutation of FoxP3 in the thymus stroma leads to defective thymopoiesis.
abstract: 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.
authors.affiliation: Division of Cancer Immunology, Department of Pathology and Comprehensive Cancer Center, Ohio State University Medical Center, Columbus, OH 43210, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Chang
authors.forename: Jian Xin
authors.initials: JX
authors.lastname: Gao
authors.forename: Qi
authors.initials: Q
authors.lastname: Jiang
authors.forename: Jing
authors.initials: J
authors.lastname: Wen
authors.forename: Nick
authors.initials: N
authors.lastname: Seifers
authors.forename: Lishan
authors.initials: L
authors.lastname: Su
authors.forename: Virginia L
authors.initials: VL
authors.lastname: Godfrey
authors.forename: Tao
authors.initials: T
authors.lastname: Zuo
authors.forename: Pan
authors.initials: P
authors.lastname: Zheng
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
mesh_terms: 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*
chemical_list: D017931:DNA Primers; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D008156:Luciferases; D001973:Bromodeoxyuridine