Abstract
BackgroundCD4+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.ResultsWe 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.ConclusionSeveral 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.
Highlights
CD4+CD25+ T regulatory cells (Tregs) play an important role in regulating immune responses, and in influencing human immune diseases such as human immunodeficiency virus (HIV) infection
It has been documented that murine CD4+CD25+ Foxp3+ Tregs cannot be generated from peripheral CD4+CD25- naive T cells by TCR plus CD28 costimulation [10,11,12,13,14] unless exogenous TGF-β is included in the cultures [10,12,15]
TCR stimulation of CD4+CD25- T cells with plate-coated anti-CD3 antibody induced detectable Foxp3 mRNA as determined by real-time PCR (Fig. 1A) and protein by Western blot (Fig. 1B) and intracellular Foxp3 staining by flow cytometry (Fig. 1C)
Summary
CD4+CD25+ T regulatory cells (Tregs) play an important role in regulating immune responses, and in influencing human immune diseases such as HIV infection. In humans, some studies have indicated that stimulation of human peripheral CD4+CD25- T cells with anti-TCR and anti-CD28 antibodies can generate CD4+CD25+ T regulatory cells that express Foxp and are immunosuppressive [16,17]. These findings, still controversial [15,18], have raised a critical issue, namely, how to reconcile the observed induction of Foxp and Tregs with the established paradigm that the primary goal of T cell activation by TCR and CD28 is to induce T cell proliferation and differentiation to mount specific T cell immunity [19]? Since TGF-β has been implicated in the induction of Tregs in murine cells, we set out to investigate whether TGF-β has a role in the unexpected induction of Tregs by TCR stimulation in human T cells
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