Endogenous TGF-beta activation by reactive oxygen species is key to Foxp3 induction in TCR-stimulated and HIV-1-infected human CD4+CD25- T cells

Retrovirology. 2007 Aug 9;4:57. doi: 10.1186/1742-4690-4-57.


Background: CD4+CD25+ T regulatory cells (Tregs) play an important role in regulating immune responses, and in influencing human immune diseases such as HIV infection. It has been shown that human CD4+CD25+ Tregs can be induced in vitro by TCR stimulation of CD4+CD25- T cells. However, the mechanism remains elusive, and intriguingly, similar treatment of murine CD4+CD25- cells did not induce CD4+CD25+Foxp3+ Tregs unless exogenous TGF-beta was added during stimulation. Thus, we investigated the possible role of TGF-beta in the induction of human Tregs by TCR engagement. We also explored the effects of TGF-beta on HIV-1 infection mediated induction of human Tregs since recent evidence has suggested that HIV-1 infection may also impact the generation of Tregs in infected patients.

Results: We show here that endogenous TGF-beta is key to TCR induction of Foxp3 in human CD4+CD25- T cells. These events involve, first, the production of TGF-beta by TCR and CD28 stimulation and the activation of latent TGF-beta by reactive oxygen species generated from the activated T cells. Biologically active TGF-beta then engages in the induction of Foxp3. Neutralization of active TGF-beta with anti-TGF-beta antibody or elimination of ROS with MnTBAP abrogated Foxp3 expression. HIV-1 infection enhanced Foxp3 expression in activated CD4+CD25- T cells; which was also abrogated by blockade of endogenous TGF-beta.

Conclusion: Several conclusions can be drawn from this work: (1) TCR and CD28-induced Foxp3 expression is a late event following TCR stimulation; (2) TGF-beta serves as a link in Foxp3 induction in human CD4+CD25- T cells following TCR stimulation, which induces not only latent, but also active TGF-beta; (3) the activation of TGF-beta requires reactive oxygen species; (4) HIV infection results in an increase in Foxp3 expression in TCR-activated CD25- T cells, which is also associated with TGF-beta. Taken together, our findings reinforce a definitive role of TGF-beta not only in the generation of Tregs with respect to normal immune responses, but also is critical in immune diseases such as HIV-1 infection.

Publication types

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

MeSH terms

  • CD4-Positive T-Lymphocytes / metabolism*
  • CD4-Positive T-Lymphocytes / virology
  • Cell Line
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Genes, T-Cell Receptor / genetics
  • Genes, T-Cell Receptor / physiology*
  • HIV Infections / immunology
  • HIV-1 / genetics
  • HIV-1 / physiology
  • Humans
  • Reactive Oxygen Species / metabolism*
  • T-Lymphocytes
  • T-Lymphocytes, Regulatory / immunology
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*


  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Reactive Oxygen Species
  • Transforming Growth Factor beta