Phosphatase Wip1 is essential for the maturation and homeostasis of medullary thymic epithelial cells in mice.
J Immunol
; 191(6): 3210-20, 2013 Sep 15.
Article
em En
| MEDLINE
| ID: mdl-23966632
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 moleculeâºUlex europaeus agglutinin-1 (UEA-1)âºmTECs, including UEA-1âºMHC class II(high), UEA-1âºCD80âº, UEA-1âºCD40âº, and UEA-1âºAire⺠cells, but not decreased numbers of cortical epithelial cell adhesion moleculeâºBP-1⺠TECs, in the postnatal stage but not in the fetal stage. Wip1-deficient mTECs express fewer tissue-restricted Ags and UEA-1âºinvolucrin⺠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.
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Base de dados:
MEDLINE
Assunto principal:
Timo
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Diferenciação Celular
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Fosfoproteínas Fosfatases
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Células Epiteliais
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Homeostase
Limite:
Animals
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article