Sex steroid blockade enhances thymopoiesis by modulating Notch signaling

J Exp Med. 2014 Nov 17;211(12):2341-9. doi: 10.1084/jem.20131289. Epub 2014 Oct 20.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Calcium-Binding Proteins
  • Cell Line
  • Dihydrotestosterone / pharmacology
  • Dose-Response Relationship, Drug
  • Epithelial Cells / drug effects
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism
  • Female
  • Flow Cytometry
  • Gonadal Steroid Hormones / antagonists & inhibitors
  • Gonadal Steroid Hormones / immunology*
  • HEK293 Cells
  • Hormone Antagonists / pharmacology
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / immunology*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lymphopoiesis / drug effects
  • Lymphopoiesis / immunology
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology*
  • Membrane Proteins / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenylthiohydantoin / analogs & derivatives
  • Phenylthiohydantoin / pharmacology
  • Receptors, Androgen / immunology
  • Receptors, LHRH / agonists
  • Receptors, LHRH / antagonists & inhibitors
  • Receptors, LHRH / immunology
  • Receptors, Notch / immunology*
  • Receptors, Notch / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / immunology*
  • Testosterone / blood
  • Testosterone / immunology
  • Thymocytes / cytology
  • Thymocytes / immunology*
  • Thymus Gland / cytology
  • Thymus Gland / immunology

Substances

  • Adaptor Proteins, Signal Transducing
  • Calcium-Binding Proteins
  • DLL4 protein, mouse
  • Gonadal Steroid Hormones
  • Hormone Antagonists
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Receptors, Androgen
  • Receptors, LHRH
  • Receptors, Notch
  • Dihydrotestosterone
  • Phenylthiohydantoin
  • Testosterone
  • enzalutamide