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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.
Afiliación
  • Velardi E; Immunology Program, Department of Medicine, and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 Department of Clinical and Experimental Medicine, University of Perugia, 06122 Perugia, Italy velardie@mskcc.org dudakovj@mskcc.org vandenbm@mskcc.org.
  • Tsai JJ; Immunology Program, Department of Medicine, and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10021.
  • Holland AM; Immunology Program, Department of Medicine, and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10021 MRC Centre for Immune Regulation, Institute for Biomedical Resea
  • Wertheimer T; Immunology Program, Department of Medicine, and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 Division of Hematology and Oncology, Department of Medicine, Freiburg University Medical Center, Albert-Ludwigs-University, 79106 Freiburg, Germany.
  • Yu VW; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114 Harvard Stem Cell Institute, Cambridge, MA 02138 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138.
  • Zakrzewski JL; Immunology Program, Department of Medicine, and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 Immunology Program, Department of Medicine, and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
  • Tuckett AZ; Immunology Program, Department of Medicine, and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
  • Singer NV; Immunology Program, Department of Medicine, and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
  • West ML; Immunology Program, Department of Medicine, and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
  • Smith OM; Immunology Program, Department of Medicine, and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
  • Young LF; Immunology Program, Department of Medicine, and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
  • Kreines FM; Immunology Program, Department of Medicine, and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
  • Levy ER; Immunology Program, Department of Medicine, and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
  • Boyd RL; Department of Anatomy and Developmental Biology, Monash University, Melbourne 3800, Australia.
  • Scadden DT; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114 Harvard Stem Cell Institute, Cambridge, MA 02138 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138.
  • Dudakov JA; Immunology Program, Department of Medicine, and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 Department of Anatomy and Developmental Biology, Monash University, Melbourne 3800, Australia velardie@mskcc.org dudakovj@mskcc.org vandenbm@mskcc.org.
  • van den Brink MR; Immunology Program, Department of Medicine, and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 Immunology Program, Department of Medicine, and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 Department of Immunology and Micro
J Exp Med ; 211(12): 2341-9, 2014 Nov 17.
Article en En | MEDLINE | ID: mdl-25332287
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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Hormonas Esteroides Gonadales / Transducción de Señal / Péptidos y Proteínas de Señalización Intracelular / Receptores Notch / Timocitos / Proteínas de la Membrana Idioma: En Revista: J Exp Med Año: 2014 Tipo del documento: Article Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Hormonas Esteroides Gonadales / Transducción de Señal / Péptidos y Proteínas de Señalización Intracelular / Receptores Notch / Timocitos / Proteínas de la Membrana Idioma: En Revista: J Exp Med Año: 2014 Tipo del documento: Article Pais de publicación: Estados Unidos