Identification of embryonic precursor cells that differentiate into thymic epithelial cells expressing autoimmune regulator

J Exp Med. 2016 Jul 25;213(8):1441-58. doi: 10.1084/jem.20151780. Epub 2016 Jul 11.

Abstract

Medullary thymic epithelial cells (mTECs) expressing autoimmune regulator (Aire) are critical for preventing the onset of autoimmunity. However, the differentiation program of Aire-expressing mTECs (Aire(+) mTECs) is unclear. Here, we describe novel embryonic precursors of Aire(+) mTECs. We found the candidate precursors of Aire(+) mTECs (pMECs) by monitoring the expression of receptor activator of nuclear factor-κB (RANK), which is required for Aire(+) mTEC differentiation. pMECs unexpectedly expressed cortical TEC molecules in addition to the mTEC markers UEA-1 ligand and RANK and differentiated into mTECs in reaggregation thymic organ culture. Introduction of pMECs in the embryonic thymus permitted long-term maintenance of Aire(+) mTECs and efficiently suppressed the onset of autoimmunity induced by Aire(+) mTEC deficiency. Mechanistically, pMECs differentiated into Aire(+) mTECs by tumor necrosis factor receptor-associated factor 6-dependent RANK signaling. Moreover, nonclassical nuclear factor-κB activation triggered by RANK and lymphotoxin-β receptor signaling promoted pMEC induction from progenitors exhibiting lower RANK expression and higher CD24 expression. Thus, our findings identified two novel stages in the differentiation program of Aire(+) mTECs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Epithelial Cells / cytology
  • Epithelial Cells / immunology*
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mouse Embryonic Stem Cells / cytology
  • Mouse Embryonic Stem Cells / immunology*
  • Plant Lectins / genetics
  • Plant Lectins / immunology
  • Thymus Gland / cytology
  • Thymus Gland / immunology*
  • Transcription Factors / genetics
  • Transcription Factors / immunology*

Substances

  • APECED protein
  • Plant Lectins
  • Transcription Factors
  • Ulex europaeus lectins