14-3-3z sequesters cytosolic T-bet, upregulating IL-13 levels in T(C)2 and CD8(+) lymphocytes from patients with scleroderma.
14-3-3z sequesters cytosolic T-bet, upregulating IL-13 levels in T(C)2 and CD8(+) lymphocytes from patients with scleroderma.
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DOI：
10.1016/j.jaci.2017.10.029
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发表时间：
2018-07
期刊：
影响因子：
--
通讯作者：
Fuschiotti P
中科院分区：
文献类型：
--
作者：
Cascio S;Medsger TA Jr;Hawse WF;Watkins SC;Milcarek C;Moreland LW;Lafyatis RA;Fuschiotti P
产生白细胞介素（IL）-13的CD 8 + T细胞与2型驱动的人类炎性病症的发病机制有关。我们已经表明，CD 8 +IL-13+细胞在皮肤纤维化中起关键作用，皮肤纤维化是系统性硬化症（硬皮病; SSc）的最典型特征。然而，CD 8 + T细胞产生IL-13和其他2型细胞因子的分子机制仍不清楚。建立SSc CD 8 + T细胞过度产生IL-13的分子基础，重点是T-bet对加塔-3活性的调节，我们表明这是SSc CD 8 +IL-13+细胞过度产生IL-13的基础。采用生物化学和生物物理方法来确定从具有严重皮肤增厚的SSc患者的血液和病变皮肤分离的CD 8 + T细胞中T-bet、加塔-3和调节因子的表达和关联。ChIP分析确定了加塔-3与IL-13启动子的结合。ImageStream分析和共聚焦显微镜观察T-bet和加塔-3的亚细胞定位。小干扰RNA降低了转录水平。T-bet与SSc CD 8 + T细胞胞质溶胶中的衔接蛋白14-3- 3 z的相互作用降低了T-bet易位到细胞核中及其与加塔-3缔合的能力，从而允许更多的加塔-3结合到IL-13启动子并诱导IL-13上调。引人注目的是，我们发现这种机制也发现在2型极化的健康供体CD 8 + T细胞（Tc 2）。我们确定了一种新的分子机制，潜在的2型细胞因子产生的CD 8 + T细胞揭示了一个更完整的图片复杂的途径，导致SSc疾病的发病机制。
Interleukin(IL)-13-producing CD8+ T cells have been implicated in the pathogenesis of type-2 driven inflammatory human conditions. We have shown that CD8+IL-13+ cells play a critical role in cutaneous fibrosis, the most characteristic feature of systemic sclerosis (scleroderma; SSc). However, the molecular mechanisms underlying IL-13 and other type-2 cytokine production by CD8+ T cells remain unclear. Establish the molecular basis of IL-13 over-production by SSc CD8+ T cells, focusing on T-bet modulation of GATA-3 activity, which we showed to underlie IL-13 over-production in SSc CD8+IL-13+ cells. Biochemical and biophysical methods were employed to determine expression and association of T-bet, GATA-3 and regulatory factors in CD8+ T cells isolated from the blood and lesional skin of SSc patients with severe skin thickening. ChIP analysis determined GATA-3 binding to the IL-13 promoter. ImageStream analysis and confocal microscopy visualized the subcellular localization of T-bet and GATA-3. Transcript levels were decreased by small interfering RNAs. The interaction of T-bet with the adaptor protein 14-3-3z in the cytosol of SSc CD8+ T cells reduces T-bet translocation into the nucleus and its ability to associate with GATA-3, allowing more GATA-3 to bind to the IL-13 promoter and inducing IL-13 up-regulation. Strikingly, we show that this mechanism is also found during type-2 polarization of healthy donor CD8+ T cells (Tc2). We identified a novel molecular mechanism underlying type-2 cytokine production by CD8+ T cells revealing a more complete picture of the complex pathway leading to SSc disease pathogenesis.
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DOI：
10.1016/j.jid.2016.11.037
发表时间：
2017-05
期刊：
The Journal of investigative dermatology
影响因子：
--
作者：
Li G;Larregina AT;Domsic RT;Stolz DB;Medsger TA Jr;Lafyatis R;Fuschiotti P
通讯作者：
Fuschiotti P
影响因子：
4
作者：
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通讯作者：
Jenner RG
影响因子：
5.3
作者：
Chen, An;Lee, Sang-Myeong;Fang, Deyu
通讯作者：
Fang, Deyu
影响因子：
3.3
作者：
GANCHI, PA;SUN, SC;BALLARD, DW
通讯作者：
BALLARD, DW
影响因子：
32.4
作者：
Hegazy, Ahmed N.;Peine, Michael;Loehning, Max
通讯作者：
Loehning, Max