Autoantigen-specific interactions with CD4+ thymocytes control mature medullary thymic epithelial cell cellularity

Immunity. 2008 Sep 19;29(3):451-63. doi: 10.1016/j.immuni.2008.08.007.

Abstract

Medullary thymic epithelial cells (mTECs) are specialized for inducing central immunological tolerance to self-antigens. To accomplish this, mTECs must adopt a mature phenotype characterized by expression of the autoimmune regulator Aire, which activates the transcription of numerous genes encoding tissue-restricted self-antigens. The mechanisms that control mature Aire(+) mTEC development in the postnatal thymus remain poorly understood. We demonstrate here that, although either CD4(+) or CD8(+) thymocytes are sufficient to sustain formation of a well-defined medulla, expansion of the mature mTEC population requires autoantigen-specific interactions between positively selected CD4(+) thymocytes bearing autoreactive T cell receptor (TCR) and mTECs displaying cognate self-peptide-MHC class II complexes. These interactions also involve the engagement of CD40 on mTECs by CD40L induced on the positively selected CD4(+) thymocytes. This antigen-specific TCR-MHC class II-mediated crosstalk between CD4(+) thymocytes and mTECs defines a unique checkpoint in thymic stromal development that is pivotal for generating a mature mTEC population competent for ensuring central T cell tolerance.

Publication types

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

MeSH terms

  • Animals
  • Autoantigens / immunology*
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD40 Antigens / immunology
  • CD40 Antigens / metabolism
  • CD40 Ligand / immunology
  • CD40 Ligand / metabolism
  • Epithelial Cells / cytology
  • Epithelial Cells / immunology*
  • Epithelial Cells / metabolism
  • Humans
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / immunology
  • Nuclear Proteins / metabolism
  • Self Tolerance
  • Thymus Gland / cytology
  • Thymus Gland / immunology*
  • Thymus Gland / metabolism
  • Trans-Activators / immunology
  • Trans-Activators / metabolism
  • Transcription Factors / immunology
  • Transcription Factors / metabolism*

Substances

  • APECED protein
  • Autoantigens
  • CD40 Antigens
  • MHC class II transactivator protein
  • Nuclear Proteins
  • Trans-Activators
  • Transcription Factors
  • CD40 Ligand