Sex steroid blockade enhances thymopoiesis by modulating Notch signaling. Academic Article uri icon

Overview

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 date

  • October 20, 2014

Research

keywords

  • Gonadal Steroid Hormones
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Receptors, Notch
  • Signal Transduction
  • Thymocytes

Identity

PubMed Central ID

  • PMC4235646

Scopus Document Identifier

  • 84911946540

Digital Object Identifier (DOI)

  • 10.1084/jem.20131289

PubMed ID

  • 25332287

Additional Document Info

volume

  • 211

issue

  • 12