Stat3 activation plays a role in mTEC development (64.20)

Abstract The thymic medulla is central to the establishment of central tolerance. Development of medullary thymic epitthelial cells (mTECs) in the fetal thymus requires lymphoid tissue inducer cells, whereas in the adult, signals from positively selected thymocytes engage different components of NF-κB signaling pathway to regulate the formation of an optimal medullary stromal niche. Thus, mTEC development is impaired in RAG-1-/- and RAG-2-/- mice due to the early block in thymocyte differentiation. We find that introduction of a constitutively active Stat3 transgene regulated by a keratin 5 promoter (K5.Stat3C) in Rag 2-/- mice rescues mTEC development bypassing the requirement for positively selected thymocytes. Although K5.Stat3C mice exhibit thymus hypoplasia, the medullary compartment is expanded. Immunohistochemical analysis demonstrates K5+K14+ and UEA+ mTECs. However, FACS analysis reveals an increase in immature mTECs based on low expression of MHC class II and CD80 markers, as well as a higher mTEC to cTEC ratio. The results suggest a partial block in the terminal differentiation of the expanded immature mTEC population. Conditional deletion of Stat3 in mTECs, achieved by crossing Stat3fl/fl mice with K5.Cre mice, leads to a decrease in mTEC cellularity and a reduced mTEC to cTEC ratio. These findings implicate a novel role for Stat3 signaling in molecular regulation of the thymic mTEC compartment.