How defects in central tolerance impinge on a deficiency in regulatory T cells

Zhibin Chen, Christophe Benoist, Diane Mathis

Research output: Contribution to journalArticlepeer-review

100 Scopus citations


Both central (thymic) and peripheral (nonthymic) mechanisms are important for the induction and maintenance of T cell tolerance. Mice with a defect in Foxp3, required for the generation and activity of CD4+CD25 + regulatory T cells, exhibit massive lymphoproliferation and severe inflammatory infiltration of multiple organs, in particular the lungs, liver, and skin. We have explored how this phenotype is influenced by an additional defect in central tolerance induction, generated by either crossing in a null mutation of the Aire gene or substituting the nonobese diabetic (NOD) genetic background. The double-deficient mice had fulminant autoimmunity in very early life and a gravely shortened lifespan vis-à-vis single-deficient littermates. They showed massive lymphoproliferation and exacerbated inflammatory damage, particularly in the lungs and liver. Yet, the range of affected sites was not noticeably extended, and, surprisingly, many organs, or regions of organs, remained untouched, suggesting additional important mechanisms to enforce immunological self-tolerance.

Original languageEnglish (US)
Pages (from-to)14735-14740
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number41
StatePublished - Oct 11 2005
Externally publishedYes


  • Aire
  • Autoimmunity
  • Central tolerance
  • Foxp3
  • Peripheral regulation

ASJC Scopus subject areas

  • Genetics
  • General


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