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Sex steroid blockade enhances thymopoiesis by modulating Notch signaling

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 s...

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Autores principales: Velardi, Enrico, Tsai, Jennifer J., Holland, Amanda M., Wertheimer, Tobias, Yu, Vionnie W.C., Zakrzewski, Johannes L., Tuckett, Andrea Z., Singer, Natalie V., West, Mallory L., Smith, Odette M., Young, Lauren F., Kreines, Fabiana M., Levy, Emily R., Boyd, Richard L., Scadden, David T., Dudakov, Jarrod A., van den Brink, Marcel R.M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4235646/
https://www.ncbi.nlm.nih.gov/pubmed/25332287
http://dx.doi.org/10.1084/jem.20131289
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author Velardi, Enrico
Tsai, Jennifer J.
Holland, Amanda M.
Wertheimer, Tobias
Yu, Vionnie W.C.
Zakrzewski, Johannes L.
Tuckett, Andrea Z.
Singer, Natalie V.
West, Mallory L.
Smith, Odette M.
Young, Lauren F.
Kreines, Fabiana M.
Levy, Emily R.
Boyd, Richard L.
Scadden, David T.
Dudakov, Jarrod A.
van den Brink, Marcel R.M.
author_facet Velardi, Enrico
Tsai, Jennifer J.
Holland, Amanda M.
Wertheimer, Tobias
Yu, Vionnie W.C.
Zakrzewski, Johannes L.
Tuckett, Andrea Z.
Singer, Natalie V.
West, Mallory L.
Smith, Odette M.
Young, Lauren F.
Kreines, Fabiana M.
Levy, Emily R.
Boyd, Richard L.
Scadden, David T.
Dudakov, Jarrod A.
van den Brink, Marcel R.M.
author_sort Velardi, Enrico
collection PubMed
description 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.
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spelling pubmed-42356462015-05-17 Sex steroid blockade enhances thymopoiesis by modulating Notch signaling Velardi, Enrico Tsai, Jennifer J. Holland, Amanda M. Wertheimer, Tobias Yu, Vionnie W.C. Zakrzewski, Johannes L. Tuckett, Andrea Z. Singer, Natalie V. West, Mallory L. Smith, Odette M. Young, Lauren F. Kreines, Fabiana M. Levy, Emily R. Boyd, Richard L. Scadden, David T. Dudakov, Jarrod A. van den Brink, Marcel R.M. J Exp Med Brief Definitive Report 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. The Rockefeller University Press 2014-11-17 /pmc/articles/PMC4235646/ /pubmed/25332287 http://dx.doi.org/10.1084/jem.20131289 Text en © 2014 Velardi et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Brief Definitive Report
Velardi, Enrico
Tsai, Jennifer J.
Holland, Amanda M.
Wertheimer, Tobias
Yu, Vionnie W.C.
Zakrzewski, Johannes L.
Tuckett, Andrea Z.
Singer, Natalie V.
West, Mallory L.
Smith, Odette M.
Young, Lauren F.
Kreines, Fabiana M.
Levy, Emily R.
Boyd, Richard L.
Scadden, David T.
Dudakov, Jarrod A.
van den Brink, Marcel R.M.
Sex steroid blockade enhances thymopoiesis by modulating Notch signaling
title Sex steroid blockade enhances thymopoiesis by modulating Notch signaling
title_full Sex steroid blockade enhances thymopoiesis by modulating Notch signaling
title_fullStr Sex steroid blockade enhances thymopoiesis by modulating Notch signaling
title_full_unstemmed Sex steroid blockade enhances thymopoiesis by modulating Notch signaling
title_short Sex steroid blockade enhances thymopoiesis by modulating Notch signaling
title_sort sex steroid blockade enhances thymopoiesis by modulating notch signaling
topic Brief Definitive Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4235646/
https://www.ncbi.nlm.nih.gov/pubmed/25332287
http://dx.doi.org/10.1084/jem.20131289
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