Both Treg cells and Tconv cells are defective in the Myasthenia gravis thymus: Roles of IL-17 and TNF-α
Both Treg cells and Tconv cells are defective in the Myasthenia gravis thymus: Roles of IL-17 and TNF-α
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DOI：
10.1016/j.jaut.2013.12.015
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发表时间：
2014-08-01
影响因子：
12.8
通讯作者：
Berrih-Aknin, Sonia
中科院分区：
文献类型：
--
作者：
Gradolatto, Angeline;Nazzal, Dani;Berrih-Aknin, Sonia
重症肌无力（MG）是一种自身免疫性疾病，其中胸腺经常呈现滤泡增生和炎症体征，T细胞显示抑制性调节缺陷。抑制性测定中的缺陷可以指示Treg细胞的功能缺陷或Tconv细胞对Treg细胞抑制的抗性。本研究的目的是确定哪些细胞负责这种缺陷，并解决所涉及的mechanism.We首先进行交叉实验研究，使用纯化的胸腺Treg细胞和Tconv细胞从控制（CTRL）和MG患者。我们证实了MG Treg细胞在抑制CTRL Tconv增殖方面存在缺陷，并且我们首次证明了MG Tconv细胞对Treg细胞抑制具有抗性。MG Tconv细胞的活化触发了比CTRL细胞更低的FoxP 3上调和更高的CD 4和CD 25上调。为了研究可以解释这些差异的因素，我们分析了来自MG患者的纯化胸腺Treg和Tconv细胞与CTRL细胞的转录组。这项分析揭示的许多途径涉及其他自身免疫性疾病，MG患者的T细胞表现出Th 1/Th 17/Tfh特征。仅在Treg细胞中观察到IL-17相关基因的增加，而在Treg和Tconv细胞中均观察到IFN-γ、IL-21和TNF-α的增加。这些结果通过PCR研究得到证实。此外，功能研究进一步证实了TNF-α在MG患者Tconv细胞缺陷中的作用，我们的结果表明MG患者的免疫调节缺陷是由Treg细胞和Tconv细胞损伤引起的，并涉及多种促炎细胞因子，其中TNF-α起着关键作用。MG患者胸腺中存在的慢性炎症可以为MG胸腺中胸腺T细胞逃避调节提供解释。(C)2013爱思唯尔有限公司保留所有权利。
Myasthenia gravis (MG) is an autoimmune disease in which the thymus frequently presents follicular hyperplasia and signs of inflammation and T cells display a defect in suppressive regulation. Defects in a suppressive assay can indicate either the defective function of Treg cells or the resistance of Tconv cells to suppression by Treg cells. The aim of this study was to determine which cells were responsible for this defect and to address the mechanisms involved.We first performed cross-experiment studies using purified thymic Treg cells and Tconv cells from controls (CTRL) and MG patients. We confirmed that MG Treg cells were defective in suppressing CTRL Tconv proliferation, and we demonstrated for the first time that MG Tconv cells were resistant to Treg cell suppression. The activation of MG Tconv cells triggered a lower upregulation of FoxP3 and a higher upregulation of CD4 and CD25 than CTRL cells. To investigate the factors that could explain these differences, we analyzed the transcriptomes of purified thymic Treg and Tconv cells from MG patients in comparison to CTRL cells. Many of the pathways revealed by this analysis are involved in other autoimmune diseases, and T cells from MG patients exhibit a Th1/Th17/Tfh signature. An increase in IL-17-related genes was only observed in Treg cells, while increases in IFN-gamma, IL-21, and TNF-alpha were observed in both Treg and Tconv cells. These results were confirmed by PCR studies. In addition, the role of TNF-alpha in the defect in Tconv cells from MG patients was further confirmed by functional studies.Altogether, our results indicate that the immunoregulatory defects observed in MG patients are caused by both Treg cell and Tconv cell impairment and involve several pro-inflammatory cytokines, with TNF-alpha playing a key role in this process. The chronic inflammation present in the thymus of MG patients could provide an explanation for the escape of thymic T cells from regulation in the MG thymus. (C) 2013 Elsevier Ltd. All rights reserved.