title: Sex steroid blockade enhances thymopoiesis by modulating Notch signaling.
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.
authors.affiliation: 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.
authors.forename: Enrico
authors.initials: E
authors.lastname: Velardi
authors.affiliation: 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.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Tsai
authors.affiliation: 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 Research, Medical School, University of Birmingham, Birmingham B15 2TT, England, UK.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Holland
authors.affiliation: 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.
authors.forename: Tobias
authors.initials: T
authors.lastname: Wertheimer
authors.affiliation: 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.
authors.forename: Vionnie W C
authors.initials: VW
authors.lastname: Yu
authors.affiliation: 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.
authors.forename: Johannes L
authors.initials: JL
authors.lastname: Zakrzewski
authors.affiliation: Immunology Program, Department of Medicine, and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Andrea Z
authors.initials: AZ
authors.lastname: Tuckett
authors.affiliation: Immunology Program, Department of Medicine, and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Natalie V
authors.initials: NV
authors.lastname: Singer
authors.affiliation: Immunology Program, Department of Medicine, and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Mallory L
authors.initials: ML
authors.lastname: West
authors.affiliation: Immunology Program, Department of Medicine, and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Odette M
authors.initials: OM
authors.lastname: Smith
authors.affiliation: Immunology Program, Department of Medicine, and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Lauren F
authors.initials: LF
authors.lastname: Young
authors.affiliation: Immunology Program, Department of Medicine, and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Fabiana M
authors.initials: FM
authors.lastname: Kreines
authors.affiliation: Immunology Program, Department of Medicine, and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Levy
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Melbourne 3800, Australia.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Boyd
authors.affiliation: 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.
authors.forename: David T
authors.initials: DT
authors.lastname: Scadden
authors.affiliation: 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.
authors.forename: Jarrod A
authors.initials: JA
authors.lastname: Dudakov
authors.affiliation: 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 Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10021 velardie@mskcc.org dudakovj@mskcc.org vandenbm@mskcc.org.
authors.forename: Marcel R M
authors.initials: MR
authors.lastname: van den Brink
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001549:Benzamides; D002135:Calcium-Binding Proteins; D002460:Cell Line; D013196:Dihydrotestosterone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D012739:Gonadal Steroid Hormones / Q000037:antagonists & inhibitors / Q000276:immunology*; D057809:HEK293 Cells; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D038041:Lymphopoiesis / Q000187:drug effects / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D011944:Receptors, Androgen / Q000276:immunology; D011966:Receptors, LHRH / Q000819:agonists / Q000037:antagonists & inhibitors / Q000276:immunology; D051880:Receptors, Notch / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013739:Testosterone / Q000097:blood / Q000276:immunology; D060168:Thymocytes / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001549:Benzamides; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D012739:Gonadal Steroid Hormones; D006727:Hormone Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009570:Nitriles; D011944:Receptors, Androgen; D011966:Receptors, LHRH; D051880:Receptors, Notch; D013196:Dihydrotestosterone; D010669:Phenylthiohydantoin; D013739:Testosterone; C540278:enzalutamide