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 IIhigh, 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.