Selection of Foxp3+ Regulatory T Cells Specific for Self Antigen Expressed and Presented by Aire+ Medullary Thymic Epithelial Cells

Nat Immunol. 2007 Apr;8(4):351-8. doi: 10.1038/ni1444. Epub 2007 Feb 25.

Abstract

The parameters specifying whether autoreactive CD4(+) thymocytes are deleted (recessive tolerance) or differentiate into regulatory T cells (dominant tolerance) remain unresolved. Dendritic cells directly delete thymocytes, partly through cross-presentation of peripheral antigens 'promiscuously' expressed in medullary thymic epithelial cells (mTECs) positive for the autoimmune regulator Aire. It is unclear if and how mTECs themselves act as antigen-presenting cells during tolerance induction. Here we found that an absence of major histocompatibility class II molecules on mTECs resulted in fewer polyclonal regulatory T cells. Furthermore, targeting of a model antigen to Aire(+) mTECs led to the generation of specific regulatory T cells independently of antigen transfer to dendritic cells. Thus, 'routing' of mTEC-derived self antigens may determine whether specific thymocytes are deleted or enter the regulatory T cell lineage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation / immunology
  • Autoantigens / immunology*
  • Cell Differentiation / immunology
  • Dendritic Cells / immunology
  • Epithelial Cells / immunology
  • Flow Cytometry
  • Forkhead Transcription Factors / immunology*
  • Hemagglutinins / immunology
  • Histocompatibility Antigens Class II / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Nude
  • Mice, Transgenic
  • Microscopy, Fluorescence
  • Receptors, Antigen, T-Cell / immunology
  • Self Tolerance / immunology
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*
  • Thymus Gland / cytology
  • Thymus Gland / immunology*
  • Transcription Factors / immunology*

Substances

  • APECED protein
  • Autoantigens
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Hemagglutinins
  • Histocompatibility Antigens Class II
  • Receptors, Antigen, T-Cell
  • Transcription Factors