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.
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.
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DOI：
10.1186/1742-4690-4-57
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发表时间：
2007-08-09
期刊：
影响因子：
3.3
通讯作者：
Chen, WanJun
中科院分区：
文献类型：
--
作者：
Amarnath, Shoba;Dong, Li;Li, Jun;Wu, Yuntao;Chen, WanJun
CD4 + CD25+调节性T细胞（Treatment cells，TCRs）在调节免疫应答中发挥重要作用，并影响人类免疫疾病如HIV感染。已经显示，人CD4 + CD25 + T细胞可以通过CD4 + CD25-T细胞的TCR刺激在体外诱导。然而，该机制仍然难以捉摸，并且有趣的是，除非在刺激期间加入外源性TGF-β，否则对鼠CD4 + CD25-细胞的类似处理不会诱导CD4 + CD25 + Foxp3 + T细胞。因此，我们研究了TGF-β在通过TCR接合诱导人TCR中的可能作用。我们还探索了TGF-β对HIV-1感染介导的人TcB诱导的影响，因为最近的证据表明HIV-1感染也可能影响感染患者中TcB的产生。我们在此表明，内源性TGF-β是人CD4 + CD25-T细胞中Foxp3的TCR诱导的关键。这些事件涉及，首先，通过TCR和⑶ 28刺激产生TGF-β以及通过由活化的T细胞产生的活性氧物质活化潜伏的TGF-β。生物活性TGF-β然后参与Foxp3的诱导。用抗TGF-β抗体中和活性TGF-β或用MnTBAP消除ROS消除Foxp3表达。HIV-1感染增强了活化的CD 4 + CD 25-T细胞中Foxp3的表达;这也被内源性TGF-β的阻断所消除。结论：（1）TCR和CD28诱导的Foxp3表达是TCR刺激后的晚期事件;（2）TGF-β是TCR刺激后人CD4 + CD25-T细胞Foxp3诱导的一个环节，它不仅诱导潜伏性TGF-β，而且诱导活性TGF-β;（3）TGF-β的激活需要活性氧;（4）HIV感染导致TCR活化的CD25-T细胞中Foxp3表达增加，这也与TGF-β相关。综上所述，我们的研究结果加强了TGF-β的决定性作用，不仅在正常免疫反应中产生THBG，而且在免疫疾病如HIV-1感染中也至关重要。
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. 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. 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.
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影响因子：
32.4
作者：
Fontenot, JD;Rasmussen, JP;Rudensky, AY
通讯作者：
Rudensky, AY
影响因子：
15.3
作者：
Apostolou, I;von Boehmer, H
通讯作者：
von Boehmer, H
影响因子：
4.4
作者：
Andersson, J;Boasso, A;Chougnet, CA
通讯作者：
Chougnet, CA
影响因子：
32.4
作者：
Chen, WJ;Frank, ME;Wahl, SM
通讯作者：
Wahl, SM
DOI：
10.1084/jem.188.10.1849
发表时间：
1998-11-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Chen W;Jin W;Wahl SM
通讯作者：
Wahl SM