Constitutive Activation of Stat3 in Thymic Epithelial Cells Drives Medullary Formation in the Thymus

Abstract

It is well established that medullary thymic epithelial cells (mTECs) play an essential role in establishing central tolerance due to their unique ability to present a diverse array of tissue restricted Ags (TSA) that induce clonal deletion of self reactive thymocytes. However, the molecular signals that drive the development of mTECs have yet to be completely defined. A previous study using epithelial specific signal transducer and activator of transcription 3 (Stat3) revealed the importance of Stat3 in postnatal maintenance of thymic architecture and thymocyte survival (Sano et al Immunity, 2001). To determine the effect of constitutive Stat3 signaling in mTECs, we examined thymic development in mice that express a constitutively active Stat3 transgene regulated by a keratin 5 promoter (K5 Stat3C). The thymus of adult K5.Stat3C mice was hypo‐plastic, thymocyte cellularity was reduced by 80% and mTEC compartment was markedly expanded in 4‐week‐old mice. In Rag 2−/− mice, mTEC development is severely impaired due to an early block in thymocyte differentiation. Introduction of the K5.Stat3C transgene in Rag 2−/−mice rescues mTEC development and restores TSA and chemokine expression. These findings implicate a role for Stat3 signaling in development of the mTEC compartment. This research is supported by Rothman‐Stevenson Foundation.