Velardi E, Tsai JJ, Holland AM, Wertheimer T, Yu VW, Zakrzewski JL, Tuckett AZ, Singer NV, West ML, Smith OM, Young LF, Kreines FM, Levy ER, Boyd RL, Scadden DT, Dudakov JA, van den Brink MR. 2014. Sex steroid blockade enhances thymopoiesis by modulating Notch signaling. The Journal of experimental medicine. 211(12):2341-9. Pubmed: 25332287 DOI:10.1084/jem.20131289


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.
© 2014 Velardi et al.

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David Scadden’s laboratory is dedicated to discovering the principles governing blood cell production, with the ultimate goal of guiding the development of therapies for blood disorders and cancer.

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