Regulatory T cells require mammalian target of rapamycin signaling to maintain both homeostasis and alloantigen-driven proliferation in lymphocyte-replete mice.
Regulatory T cells require mammalian target of rapamycin signaling to maintain both homeostasis and alloantigen-driven proliferation in lymphocyte-replete mice.
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DOI：
10.4049/jimmunol.0903805
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发表时间：
2011-03-01
期刊：
影响因子：
--
通讯作者：
Rothstein DM
中科院分区：
文献类型：
--
作者：
Wang Y;Camirand G;Lin Y;Froicu M;Deng S;Shlomchik WD;Lakkis FG;Rothstein DM
雷帕霉素（Rapa）是一种通过抑制哺乳动物靶点Rapa发挥作用的免疫抑制药物，在移植和自身免疫的动物模型中与致耐受剂广泛协同作用。在体外扩增过程中，Rapa优先抑制传统的CD4+ Foxp3− T细胞（Tconv），并促进CD4+Foxp3+调节性T细胞（Treg）的生长。此外，Rapa被广泛认为是增强Treg在体内的扩增和转化。然而，大多数定量研究是在淋巴细胞减少的宿主或移植物抗宿主病模型中进行的。我们在这项研究中表明，在充满野生型小鼠，拉帕显着抑制稳态和同种异体抗原诱导的Treg增殖，并促进其凋亡。总之，这些导致显著的Treg耗竭。Tconv经历类似程度的消耗，导致CD4细胞中Treg的百分比没有变化。此外，在这种情况下，没有证据表明Tconv转化为Treg。然而，在撤销Rapa后，Treg比Tconv更快地恢复Ag诱导的增殖，导致恢复到基线数量，并且与Tconv相比Treg的百分比增加。这些发现表明Rapa对Treg存活、稳态和诱导的作用在很大程度上取决于细胞环境和活化程度。在体内，Treg对哺乳动物靶Rapa抑制的抗性是相对的，并且来自淋巴细胞减少和移植物抗宿主病模型的结果不能直接外推到更典型的实体器官移植或自身免疫的环境。此外，这些结果对于使用耐受原性药物进行Rapa治疗的时机具有重要意义，该耐受原性药物旨在增加体内Treg的数量。
Rapamycin (Rapa), an immunosuppressive drug that acts through mammalian target of Rapa inhibition, broadly synergizes with tolerogenic agents in animal models of transplantation and autoimmunity. Rapa preferentially inhibits conventional CD4+ Foxp3− T cells (Tconv) and promotes outgrowth of CD4+Foxp3+ regulatory T cells (Treg) during in vitro expansion. Moreover, Rapa is widely perceived as augmenting both expansion and conversion of Treg in vivo. However, most quantitative studies were performed in lymphopenic hosts or in graft-versus-host disease models. We show in this study that in replete wild-type mice, Rapa significantly inhibits both homeostatic and alloantigen-induced proliferation of Treg, and promotes their apoptosis. Together, these lead to significant Treg depletion. Tconv undergo depletion to a similar degree, resulting in no change in the percent of Treg among CD4 cells. Moreover, in this setting, there was no evidence of conversion of Tconv into Treg. However, after withdrawal of Rapa, Treg recover Ag-induced proliferation more quickly than Tconv, leading to recovery to baseline numbers and an increase in the percent of Treg compared with Tconv. These findings suggest that the effects of Rapa on Treg survival, homeostasis, and induction, depend heavily on the cellular milieu and degree of activation. In vivo, the resistance of Treg to mammalian target of Rapa inhibition is relative and results from lymphopenic and graft-versus-host disease models cannot be directly extrapolated to settings more typical of solid organ transplantation or autoimmunity. Moreover, these results have important implications for the timing of Rapa therapy with tolerogenic agents designed to increase the number of Treg in vivo.
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影响因子：
32.4
作者：
Hill, Jonathan A.;Feuerer, Markus;Benoist, Christophe
通讯作者：
Benoist, Christophe
1型糖尿病患者的雷帕霉素单药治疗可修饰CD4+CD25+FOXP3+调节性T细胞。
影响因子：
7.7
作者：
Monti, Paolo;Scirpoli, Miriam;Maffi, Paola;Piemonti, Lorenzo;Secchi, Antonio;Bonifacio, Ezio;Roncarolo, Maria-Grazia;Battaglia, Manuela
通讯作者：
Battaglia, Manuela
介导同种异体移植耐受性的FOXP3+ T调节细胞的募集取决于CCR4趋化因子受体。
影响因子：
15.3
作者：
Lee, I;Wang, LQ;Wells, AD;Dorf, ME;Ozkaynak, E;Hancock, WW
通讯作者：
Hancock, WW
DOI：
10.1084/jem.20042020
发表时间：
2005-01-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
通讯作者：
--
影响因子：
8.8
作者：
Gao, W.;Lu, Y.;Strom, T. B.
通讯作者：
Strom, T. B.