['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.', '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.'] Is endogenous TGF-beta activation by reactive oxygen species key to Foxp3 induction in TCR-stimulated and HIV-1-infected human CD4+CD25- T cells?