A critical function for TGF-beta signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells

Nat Immunol. 2008 Jun;9(6):632-40. doi: 10.1038/ni.1607. Epub 2008 Apr 27.


The molecular mechanisms directing the development of 'natural' CD4+CD25+Foxp3+ regulatory T cells (T(reg) cells) in the thymus are not thoroughly understood. We show here that conditional deletion of transforming growth factor-beta receptor I (TbetaRI) in T cells blocked the appearance of CD4+CD25+Foxp3+ thymocytes at postnatal days 3-5. Paradoxically, however, beginning 1 week after birth, the same TbetaRI-mutant mice showed accelerated expansion of thymic CD4+CD25+Foxp3+ populations. This rapid recovery of Foxp3+ thymocytes was attributable mainly to overproduction of and heightened responsiveness to interleukin 2, as genetic ablation of interleukin 2 in TbetaRI-mutant mice resulted in a complete absence of CD4+CD25+Foxp3+ cells from the thymus and periphery. Thus, transforming growth factor-beta signaling is critical to the thymic development of natural CD4+CD25+Foxp3+ T(reg) cells.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • B-Cell Activating Factor / metabolism*
  • CD4-Positive T-Lymphocytes / metabolism
  • Forkhead Transcription Factors / analysis
  • Forkhead Transcription Factors / metabolism*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / immunology
  • Mice
  • Signal Transduction / physiology*
  • T-Lymphocytes, Regulatory / classification
  • T-Lymphocytes, Regulatory / immunology*
  • Transforming Growth Factor beta / metabolism*


  • B-Cell Activating Factor
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Transforming Growth Factor beta