An intrinsic mechanism predisposes Foxp3-expressing regulatory T cells to Th2 conversion in vivo.
An intrinsic mechanism predisposes Foxp3-expressing regulatory T cells to Th2 conversion in vivo.
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DOI：
10.4049/jimmunol.1001255
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发表时间：
2010-11-15
期刊：
影响因子：
--
通讯作者：
Wan YY
中科院分区：
文献类型：
--
作者：
Wang Y;Souabni A;Flavell RA;Wan YY
天然存在的调节性T（nTreg）细胞表达Foxp 3，并且最初被发现为对自身耐受和免疫稳态至关重要的免疫抑制剂。通过尚未定义的机制，nTreg细胞最近被证明可以转化为促炎细胞。特别地，Foxp 3表达的减弱导致体内nTreg细胞的Th 2转化。在本文中，我们展示了一个nTreg特定的机制控制他们的Th 2转换。我们发现，表达Foxp 3水平降低的野生型nTreg细胞产生Th 2细胞因子IL-4，但不表达Foxp 3的野生型nTreg细胞不产生Th 2细胞因子IL-4。有趣的是，转化的nTreg细胞产生的IL-4是体内共存的初始CD 4 T细胞的Th 2分化所必需的，这表明nTreg细胞的Th 2转化对于指导Th 2免疫应答可能是至关重要的。nTreg细胞的Th 2转化不是由于它们不能变成Th 1细胞，因为当IL-4/STAT-6信号传导被消除时，Foxp 3低表达细胞产生IFN-γ。然而，令人惊讶的是，与IL-4产生依赖于STAT-6的初始CD 4 T细胞不同，Foxp 3低表达细胞产生的IL-4不依赖于STAT-6，表明有利于nTreg向Th 2分化的内在机制。事实上，与初始CD 4 T细胞相比，nTreg表达不依赖于STAT-6的升高水平的加塔-3。而加塔-3则是nTreg向Th 2转化所必需的。Foxp 3可能是nTreg细胞中加塔-3上调的原因，因为Foxp 3的异位表达优先促进加塔-3而不是T-bet表达。因此，我们已经确定了一个内在的机制，施加一个Th 2/Th 1的不平衡，并倾向于Foxp 3表达细胞IL-4的生产独立的STAT-6信号。
Naturally occurring regulatory T (nTreg) cells express Foxp3 and were originally discovered as immune suppressors critical for self-tolerance and immune homeostasis. Through yet-to-be-defined mechanisms, nTreg cells were recently shown to convert into proinflammatory cells. Particularly, attenuation of Foxp3 expression led to Th2 conversion of nTreg cells in vivo. In this paper, we demonstrated an nTreg-specific mechanism controlling their Th2 conversion. We found that wild-type nTreg cells expressing reduced levels of Foxp3 but not those expressing no Foxp3 produced the Th2 cytokine IL-4. Intriguingly, IL-4 production by converted nTreg cells is required for Th2 differentiation of coexisting naive CD4 T cells in vivo, suggesting that Th2 conversion of nTreg cells might be critical for directing Th2 immune responses. Th2 conversion of nTreg cells was not due to their inability to become Th1 cells, because IFN-γ was produced by Foxp3-low–expressing cells when IL-4/STAT-6 signaling was abrogated. Surprisingly, however, unlike naive CD4 T cells whose IL-4 production is dependent on STAT-6, Foxp3-low–expressing cells generated IL-4 independent of STAT-6, indicating an intrinsic mechanism that favors nTreg-to-Th2 differentiation. Indeed, compared with naive CD4 T cells, nTreg expressed elevated levels of GATA-3 independent of STAT-6. And GATA-3 was required for nTreg-to-Th2 conversion. Foxp3 may account for this GATA-3 upregulation in nTreg cells, because ectopic expression of Foxp3 preferentially promoted GATA-3 but not T-bet expression. Thus, we have identified an intrinsic mechanism that imposes a Th2/Th1 imbalance and predisposes Foxp3-expressing cells to IL-4 production independent of STAT-6 signaling.
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影响因子：
64.5
作者：
Ivanov, Ivaylo I.;McKenzie, Brent S.;Littman, Dan R.
通讯作者：
Littman, Dan R.
影响因子：
56.9
作者：
Sommers, CL;Park, CS;Love, PE
通讯作者：
Love, PE
GATA3驱动的Th2响应抑制TGF-BETA1诱导的FOXP3表达和调节T细胞的形成。
影响因子：
9.8
作者：
Mantel PY;Kuipers H;Boyman O;Rhyner C;Ouaked N;Rückert B;Karagiannidis C;Lambrecht BN;Hendriks RW;Crameri R;Akdis CA;Blaser K;Schmidt-Weber CB
通讯作者：
Schmidt-Weber CB
DOI：
10.1073/pnas.0909357106
发表时间：
2009-10-20
影响因子：
11.1
作者：
Jenner, Richard G.;Townsend, Michael J.;Lord, Graham M.
通讯作者：
Lord, Graham M.
影响因子：
32.4
作者：
Kaplan, MH;Schindler, U;Grusby, MJ
通讯作者：
Grusby, MJ