Foxp3 interacts with nuclear factor of activated T cells and NF-κB to repress cytokine gene expression and effector functions of T helper cells
Foxp3 interacts with nuclear factor of activated T cells and NF-κB to repress cytokine gene expression and effector functions of T helper cells
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DOI：
10.1073/pnas.0501675102
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发表时间：
2005-04-05
影响因子：
11.1
通讯作者：
Oukka, M
中科院分区：
文献类型：
--
作者：
Bettelli, E;Dastrange, M;Oukka, M
缺乏功能性Foxp3的安全小鼠表现出严重的淋巴增生性疾病，并表现出细胞因子的普遍过度产生。本研究表明，在Foxp转录因子家族（包括Foxp1、Foxp2和Foxp3）中，只有Foxp3能够抑制原代T辅助细胞产生IL-2、IL-4和ifn - γ。我们发现Foxp3与Rel家族转录因子、活化T细胞核因子（NFAT）和NF-kappa B物理关联，并阻断它们诱导内源性靶基因表达的能力，包括关键细胞因子基因。更重要的是，与来自WT小鼠的T细胞相比，来自安全小鼠的T细胞具有显著增加的活化T细胞核因子（NFAT）和nf - κ B转录活性。此外，Foxp3在安全来源的T细胞中的互补降低了NFAT和NF-kappa B的转录活性到生理水平。最后，我们发现用Foxp3转导的髓磷脂蛋白脂蛋白特异性自身反应性T细胞不能介导实验性自身免疫性脑脊髓炎，进一步支持Foxp3抑制自身反应性T细胞的效应功能。Foxp3已经与CD4(+)CD25（+）调节性T细胞的产生有关；我们的数据还表明，Foxp3通过直接抑制两个关键转录因子NFAT和NF-kappa B的活性来抑制T辅助细胞的效应功能，这两个转录因子是细胞因子基因表达和T细胞功能所必需的。
Scurfy mice, which are deficient in a functional Foxp3, exhibit a severe lymphoproliferative disorder and display generalized overproduction of cytokines. Here, we show that, among the Foxp transcriptional factor family, which includes Foxp1, Foxp2, and Foxp3, only Foxp3 has the ability to inhibit IL-2, IL-4, and IFN-gamma production by primary T helper cells. We found that Foxp3 physically associates with the Rel family transcription factors, nuclear factor of activated T cells (NFAT) and NF-kappa B, and blocks their ability to induce the endogenous expression of their target genes, including key cytokine genes. More importantly, T cells derived from scurfy mice have a dramatic increase in nuclear factor of activated T cells (NFAT) and NF-kappa B transcriptional activity compared with the T cells derived from WT mice. Furthermore, complementation of Foxp3 in scurfy-derived T cells lowers the NFAT and NF-kappa B transcriptional activity to the physiological level. Finally, we show that myelin proteolipid protein-specific autoreactive T cells transduced with Foxp3 cannot mediate experimental autoimmune encephalomyelitis, providing further support that Foxp3 suppresses the effector function of autoreactive T cells. Foxp3 has already been associated with the generation of CD4(+)CD25(+) regulatory T cells; our data additionally demonstrate that Foxp3 suppresses the effector functions of T helper cells by directly inhibiting the activity of two key transcription factors, NFAT and NF-kappa B, which are essential for cytokine gene expression and T cell functions.