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

Lookup NU author(s): Dr Shoba AmarnathORCiD


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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-β was added during stimulation. Thus, we investigated the possible role of TGF-β in the induction of human Tregs by TCR engagement. We also explored the effects of TGF-β 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-β is key to TCR induction of Foxp3 in human CD4+CD25-T cells. These events involve, first, the production of TGF-β by TCR and CD28 stimulation and the activation of latent TGF-β by reactive oxygen species generated from the activated T cells. Biologically active TGF-β then engages in the induction of Foxp3. Neutralization of active TGF-β with anti-TGF-β 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-β. 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-β 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-β; (3) the activation of TGF-β 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-β. Taken together, our findings reinforce a definitive role of TGF-β 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. © 2007 Amarnath et al; licensee BioMed Central Ltd.

Publication metadata

Author(s): Amarnath S, Dong L, Li J, Wu Y, Chen WJ

Publication type: Article

Publication status: Published

Journal: Retrovirology

Year: 2007

Volume: 4

Online publication date: 09/08/2007

ISSN (electronic): 1742-4690

Publisher: BioMed Central Ltd.


DOI: 10.1186/1742-4690-4-57

PubMed id: 17688698


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