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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...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2014
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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. |
format | Online Article Text |
id | pubmed-4235646 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
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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