GARP-TGF-β complexes negatively regulate regulatory T cell development and maintenance of peripheral CD4+ T cells in vivo.
GARP-TGF-β complexes negatively regulate regulatory T cell development and maintenance of peripheral CD4+ T cells in vivo.
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DOI：
10.4049/jimmunol.1300065
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发表时间：
2013-05-15
期刊：
影响因子：
--
通讯作者：
Unutmaz D
中科院分区：
文献类型：
--
作者：
Zhou AX;Kozhaya L;Fujii H;Unutmaz D
表面结合的 TGFβ 对调节性 T 细胞 (Treg) 的作用以及介导其功能的机制尚未明确。我们最近发现了一种称为 GARP 的细胞表面分子，它在激活的 Tregs 上特异性表达，并被发现与潜在的 TGFβ 结合并在体外介导部分 Treg 抑制活性。在这里，我们使用在所有 T 细胞上表达 GARP 的转基因小鼠来探讨 GARP 在调节 Treg 和常规 T 细胞发育以及体内免疫抑制中的作用。我们发现，尽管 GARP 在所有 T 细胞上强制表达，但需要通过 T 细胞受体 (TCR) 进行刺激才能将 GARP 有效定位到细胞表面。此外，IL-2 信号增强了 GARP 细胞表面表达，特别是在 Tregs 上。 GARP 转基因 CD4+ T 细胞和 Tregs，尤其是那些表达较高水平 GARP 的细胞，在外周显着减少。胸腺中成熟的 Tregs（而非传统的 CD4+ T 细胞）也减少了。 CD4+ T 细胞减少在效应/记忆亚群中更为明显，尤其是随着小鼠年龄的增长。此外，通过 TCR 刺激的 GARP 过表达 CD4+ T 细胞表现出增殖能力降低，但通过抑制 TGFβ 信号传导可以恢复增殖能力。此外，抑制 TGFβ 信号极大地增强了 Tregs 上 GARP 的表面表达，并阻断了过表达 GARP 的活化 CD4+ T 细胞中 FoxP3 的诱导。这些发现表明，GARP 通过激活结合的潜在 TGFβ 和信号传导，在自然和诱导的 Treg 发育中发挥作用，从而负向调节 Tregs 上的 GARP 表达。
The role of surface bound TGFβ on regulatory T cells (Tregs) and the mechanisms mediating its functions are not well defined. We recently identified a cell surface molecule called GARP, which is expressed specifically on activated Tregs and was found to bind latent-TGFβ and mediate a portion of Treg suppressive activity in vitro. Here, we address the role of GARP in regulating Treg and conventional T cell development and immune suppression in vivo using a transgenic mouse expressing GARP on all T cells. We found that, despite forced expression of GARP on all T cells, stimulation through the T cell receptor (TCR) was required for efficient localization of GARP to the cell surface. In addition, IL-2 signals enhanced GARP cell surface expression specifically on Tregs. GARP-transgenic CD4+ T cells and Tregs, especially those expressing higher levels of GARP, were significantly reduced in the periphery. Mature Tregs, but not conventional CD4+ T cells, were also reduced in the thymus. CD4+ T cell reduction was more pronounced within the effector/memory subset, especially as the mouse aged. Additionally, GARP overexpressing CD4+ T cells stimulated through the TCR displayed reduced proliferative capacity, which was restored by inhibiting TGFβ signaling. Furthermore, inhibiting TGFβ signals greatly enhanced surface expression of GARP on Tregs and blocked the induction of FoxP3 in activated CD4+ T cells overexpressing GARP. These findings suggest a role for GARP in natural and induced Treg development through activation of bound latent TGFβ and signaling, which negatively regulates GARP expression on Tregs.
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影响因子：
15.3
作者：
Fahlén, L;Read, S;Gorelik, L;Hurst, SD;Coffman, RL;Flavell, RA;Powrie, F
通讯作者：
Powrie, F
影响因子：
32.4
作者：
Marie, Julien C.;Liggitt, Denny;Rudensky, Alexander Y.
通讯作者：
Rudensky, Alexander Y.
影响因子：
32.4
作者：
Gorelik, L;Flavell, RA
通讯作者：
Flavell, RA
DOI：
10.1073/pnas.0408197102
发表时间：
2005-01-11
影响因子：
11.1
作者：
Chen, ML;Pittet, MJ;Khazaie, K
通讯作者：
Khazaie, K
DOI：
10.1084/jem.163.5.1037
发表时间：
1986-05-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kehrl JH;Wakefield LM;Roberts AB;Jakowlew S;Alvarez-Mon M;Derynck R;Sporn MB;Fauci AS
通讯作者：
Fauci AS