Sex steroid blockade enhances thymopoiesis by modulating Notch signaling

Enrico Velardi, Jennifer J Tsai, Amanda M Holland, Tobias Wertheimer, Vionnie W C Yu, Johannes L Zakrzewski, Andrea Z Tuckett, Natalie V Singer, Mallory L West, Odette M Smith, Lauren F Young, Fabiana M Kreines, Emily R Levy, Richard L Boyd, David T Scadden, Jarrod Andrew Dudakov, Marcel R M van den Brink

Research output: Contribution to journalArticleResearchpeer-review

55 Citations (Scopus)

Abstract

Paradoxical to its importance for generating a diverse T cell repertoire, thymic function progressively declines throughout life. This process has been at least partially attributed to the effects of sex steroids, and their removal promotes enhanced thymopoiesis and recovery from immune injury. We show that one mechanism by which sex steroids influence thymopoiesis is through direct inhibition in cortical thymic epithelial cells (cTECs) of Delta-like 4 (Dll4), a Notch ligand crucial for the commitment and differentiation of T cell progenitors in a dose-dependent manner. Consistent with this, sex steroid ablation (SSA) led to increased expression of Dll4 and its downstream targets. Importantly, SSA induced by luteinizing hormone-releasing hormone (LHRH) receptor antagonism bypassed the surge in sex steroids caused by LHRH agonists, the gold standard for clinical ablation of sex steroids, thereby facilitating increased Dll4 expression and more rapid promotion of thymopoiesis. Collectively, these findings not only reveal a novel mechanism underlying improved thymic regeneration upon SSA but also offer an improved clinical strategy for successfully boosting immune function.
Original languageEnglish
Pages (from-to)2341 - 2349
Number of pages9
JournalJournal of Experimental Medicine
Volume211
Issue number12
DOIs
Publication statusPublished - 2014

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