Integrated T-cell receptor and costimulatory signals determine TGF-β-dependent differentiation and maintenance of Foxp3+ regulatory T cells

Eur J Immunol. 2011 May;41(5):1242-8. doi: 10.1002/eji.201041073. Epub 2011 Apr 11.


Foxp3-expressing Tregs play a non-redundant role in protecting against immune pathologies. Foxp3(+) Tregs can arise intra- and extra-thymically, however, the signals directing their differentiation and maintenance in the periphery are not well understood. We show that stimulation of mouse naïve CD4(+) T cells in vitro with optimal doses of anti-CD3/anti-CD28 resulted in high frequencies of Foxp3(+) T cells via a TGF-β-dependent mechanism. Addition of TGF-β and retinoic acid overcame the inhibition of Foxp3 expression observed during high-strength anti-CD3/anti-CD28 stimulation. Reducing the strength of TCR or costimulatory signals with inhibitors of mammalian target of rapamycin (mTOR) or MEK/ERK signalling also enhanced expression of Foxp3 in a TGF-β-dependent manner. Addition of TGF-β was further required to maintain Foxp3 expression in ex vivo derived Foxp3(+) Tregs upon prolonged anti-CD3/anti-CD28 signalling. Thus, induction/maintenance of Foxp3 expression by TGF-β is modulated by the integrated strength of TCR/costimulatory signals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing / immunology
  • CD28 Antigens / immunology
  • CD3 Complex / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Differentiation
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Flow Cytometry
  • Forkhead Transcription Factors* / antagonists & inhibitors
  • Forkhead Transcription Factors* / immunology
  • Forkhead Transcription Factors* / metabolism
  • Gene Expression
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Antigen, T-Cell / metabolism*
  • Signal Transduction
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism
  • Transforming Growth Factor beta / immunology
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta / pharmacology
  • Tretinoin / pharmacology


  • Antibodies, Neutralizing
  • CD28 Antigens
  • CD3 Complex
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Receptors, Antigen, T-Cell
  • Transforming Growth Factor beta
  • Tretinoin
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase Kinases