title: Phosphatase Wip1 is essential for the maturation and homeostasis of medullary thymic epithelial cells in mice.
abstract: Thymic epithelial cells (TECs) are a key cell type in the thymic microenvironment essential for T cell development. However, intrinsic molecular mechanisms controlling TEC differentiation and activities are poorly defined. In this study, we found that deficiency of p53-induced phosphatase 1 (Wip1) in mice selectively caused severe medullary TEC (mTEC) maturation defects in an intrinsic manner. Wip1 knockout (KO) mice had decreased mature epithelial cell adhesion molecule⁺Ulex europaeus agglutinin-1 (UEA-1)⁺mTECs, including UEA-1⁺MHC class II(high), UEA-1⁺CD80⁺, UEA-1⁺CD40⁺, and UEA-1⁺Aire⁺ cells, but not decreased numbers of cortical epithelial cell adhesion molecule⁺BP-1⁺ TECs, in the postnatal stage but not in the fetal stage. Wip1-deficient mTECs express fewer tissue-restricted Ags and UEA-1⁺involucrin⁺ terminal-differentiated cells. Animal models, including grafting fetal Wip1-deficient thymic tissue into T cell-deficient nude mice and reconstitution of lethally irradiated Wip1KO mouse recipients with wild-type bone marrow cells, also showed the impaired mTEC components in Wip1KO thymi, indicating the intrinsic regulatory role of Wip1 in mTEC maturation. Furthermore, thymus regeneration was significantly less efficient in adult Wip1KO mice than in wild-type mice after cyclophosphamide treatment. Wip1 deficiency resulted in elevated p38 MAPK activity in mTECs. Activated p38 MAPK has the ability to suppress CD40 expression on mTECs. Wip1-deficient thymi displayed poor response to CD40L in the fetal thymus organ culture system. Thus, Wip1 positively controls mTEC maturation, homeostasis, and regeneration through limiting the p38 MAPK pathway.
authors: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China 100101.
authors: Lina
authors: L
authors: Sun
authors: Hongran
authors: H
authors: Li
authors: Haiying
authors: H
authors: Luo
authors: Lianjun
authors: L
authors: Zhang
authors: Xuelian
authors: X
authors: Hu
authors: Tao
authors: T
authors: Yang
authors: Chenming
authors: C
authors: Sun
authors: Hui
authors: H
authors: Chen
authors: Lianfeng
authors: L
authors: Zhang
authors: Yong
authors: Y
authors: Zhao
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D002469:Cell Separation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006706:Homeostasis / Q000502:physiology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010749:Phosphoprotein Phosphatases / Q000276:immunology / Q000378:metabolism*; D000071636:Protein Phosphatase 2C; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D017154:Stromal Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism*
chemical_list: D010749:Phosphoprotein Phosphatases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C