Defective Th1 cytokine gene transcription in CD4+ and CD8+ T cells from Wiskott-Aldrich syndrome patients
Defective Th1 cytokine gene transcription in CD4+ and CD8+ T cells from Wiskott-Aldrich syndrome patients
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DOI：
10.4049/jimmunol.177.10.7451
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发表时间：
2006-11-15
影响因子：
4.4
通讯作者：
Dupre, Loic
中科院分区：
文献类型：
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作者：
Trifari, Sara;Sitia, Giovanni;Dupre, Loic
Wiskott-Aldrich综合征蛋白(WASP)在TCR介导的激活和免疫突触形成中起关键作用。然而，WASP缺乏对人CD4(+)和CD8(+)T细胞效应器功能的影响仍有待确定。在这项研究中，与健康供者的CD8(+)T细胞相比，AS患者的CD8(+)T细胞由TCR/CD28驱动的增殖和IL-2、干扰素-γ和肿瘤坏死因子-α的分泌显著减少。此外，CD4(+)T细胞分泌低水平的IL-2，不能产生干扰素-γ和肿瘤坏死因子-α，而对IL-4、IL-5和IL-10的产生影响很小。在Th1极化的条件下，幼稚的CD4(+)T细胞培养后仍有缺陷的IL-2和干扰素-γ的产生。Th1细胞因子产生的缺陷也存在于转录水平，表现为TCR/CD28触发后IL-2和干扰素-γ的mRNA转录减少。Th1细胞因子基因的转录减少与T-bet mRNA的缺陷诱导和NFAT-1早期核招募的减少有关，而is CD8(+)T细胞的缺陷激活与NFAT-1和NFAT-2的核招募减少相关。综上所述，我们的数据表明，WASP调节T细胞的转录激活，并且是Th1细胞因子产生所必需的。
Wiskott-Aldrich syndrome (WAS) protein (WASP) plays a key role in TCR-mediated activation and immunological synapse formation. However, the effects of WASP deficiency on effector functions of human CD4(+) and CD8(+) T cells remain to be determined. In this study, we report that TCR/CD28-driven proliferation and secretion of IL-2, IFN-gamma, and TNF-alpha are strongly reduced in CD8(+) T cells from WAS patients, compared with healthy donor CD8(+) T cells. Furthermore, WAS CD4(+) T cells secrete low levels of IL-2 and fail to produce IFN-gamma and TNF-alpha, while the production of IL-4, IL-5, and IL-10 is only minimally affected. Defective IL-2 and IFN-gamma production persists after culture of naive WAS CD4(+) T cells in Th1-polarizing conditions. The defect in Th1 cytokine production by WAS CD4(+) and CD8(+) T cells is also present at the transcriptional level, as shown by reduced IL-2 and IFN-gamma mRNA transcripts after TCR/CD28 triggering. The reduced transcription of Th1 cytokine genes in WAS CD4(+) T cells is associated with a defective induction of T-bet mRNA and a reduction in the early nuclear recruitment of NFAT-1, while the defective activation of WAS CD8(+) T cells correlates with reduced nuclear recruitment of both NFAT-1 and NFAT-2. Together, our data indicate that WASP regulates the transcriptional activation of T cells and is required specifically for Th1 cytokine production.