The Cytokine RANKL Produced by Positively Selected Thymocytes Fosters Medullary Thymic Epithelial Cells That Express Autoimmune Regulator

Immunity. 2008 Sep 19;29(3):438-50. doi: 10.1016/j.immuni.2008.06.018.

Abstract

The thymic medulla provides a microenvironment where medullary thymic epithelial cells (mTECs) express autoimmune regulator and diverse tissue-restricted genes, contributing to launching self-tolerance. Positive selection is essential for thymic medulla formation via a previously unknown mechanism. Here we show that the cytokine RANK ligand (RANKL) was produced by positively selected thymocytes and regulated the cellularity of mTEC by interacting with RANK and osteoprotegerin. Forced expression of RANKL restored thymic medulla in mice lacking positive selection, whereas RANKL perturbation impaired medulla formation. These results indicate that RANKL produced by positively selected thymocytes is responsible for fostering thymic medulla formation, thereby establishing central tolerance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmunity
  • Epithelial Cells / cytology
  • Epithelial Cells / immunology*
  • Epithelial Cells / metabolism
  • Mice
  • Osteoprotegerin / metabolism
  • RANK Ligand / metabolism*
  • Receptor Activator of Nuclear Factor-kappa B / metabolism*
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • Self Tolerance
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Thymus Gland / cytology
  • Thymus Gland / immunology*
  • Thymus Gland / metabolism
  • Transcription Factors / metabolism*

Substances

  • APECED protein
  • Osteoprotegerin
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Antigen, T-Cell
  • TNF-Related Apoptosis-Inducing Ligand
  • Transcription Factors