The transcriptional activator Gli2 modulates T-cell receptor signalling through attenuation of AP-1 and NFκB activity.
The transcriptional activator Gli2 modulates T-cell receptor signalling through attenuation of AP-1 and NFκB activity.
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转录激活因子Gli2通过减弱AP - 1和NFκB的活性来调节T细胞受体信号传导。
DOI：
10.1242/jcs.165803
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发表时间：
2015-06-01
影响因子：
4
通讯作者：
Crompton T
中科院分区：
文献类型：
--
作者：
Furmanski AL;Barbarulo A;Solanki A;Lau CI;Sahni H;Saldana JI;D'Acquisto F;Crompton T
不同的组织包含不同且动态的细胞生态位，为组织驻留或迁移浸润的免疫细胞提供不同的信号。Hedgehog（Hh）蛋白是一种分泌的细胞间信号分子，在发育过程中是必需的，并且在癌症、出生后组织稳态和修复中是重要的。由Hh应答转录因子Gli 2介导的Hh信号传导在T淋巴细胞发育和分化中也具有多种作用。在这里，我们研究了Gli 2在T细胞信号传导和激活中的功能。由Gli 2转录激活因子同种型（Gli 2A）驱动的基因转录减弱了T细胞受体（TCR）刺激后的T细胞活化和增殖。Gli 2A在T细胞中的表达改变了基因表达谱，损害了TCR诱导的Ca 2+通量和NFAT 2的核表达，抑制了活化所必需的分子的上调，并减弱了AP-1和NFκB复合物上游的信号传导途径，导致这些重要转录因子的活化减少。抑制生理性Hh依赖性转录增加TCR连接后NFκB活性。这些数据对于理解免疫调节的分子机制非常重要，特别是在Hh蛋白或其他Gli激活配体（如TGFβ）上调的组织中，包括炎症、组织损伤和修复期间以及肿瘤微环境中。
Different tissues contain diverse and dynamic cellular niches, providing distinct signals to tissue-resident or migratory infiltrating immune cells. Hedgehog (Hh) proteins are secreted inter-cellular signalling molecules, which are essential during development and are important in cancer, post-natal tissue homeostasis and repair. Hh signalling mediated by the Hh-responsive transcription factor Gli2 also has multiple roles in T-lymphocyte development and differentiation. Here, we investigate the function of Gli2 in T-cell signalling and activation. Gene transcription driven by the Gli2 transcriptional activator isoform (Gli2A) attenuated T-cell activation and proliferation following T-cell receptor (TCR) stimulation. Expression of Gli2A in T-cells altered gene expression profiles, impaired the TCR-induced Ca2+ flux and nuclear expression of NFAT2, suppressed upregulation of molecules essential for activation, and attenuated signalling pathways upstream of the AP-1 and NFκB complexes, leading to reduced activation of these important transcription factors. Inhibition of physiological Hh-dependent transcription increased NFκB activity upon TCR ligation. These data are important for understanding the molecular mechanisms of immunomodulation, particularly in tissues where Hh proteins or other Gli-activating ligands such as TGFβ are upregulated, including during inflammation, tissue damage and repair, and in tumour microenvironments.
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影响因子：
4.4
作者：
Hager-Theodorides, Ariadne L.;Furmanski, Anna L.;Crompton, Tessa
通讯作者：
Crompton, Tessa
影响因子：
11.2
作者：
Dennler, Sylviane;Andre, Jocelyne;Mauviel, Alain
通讯作者：
Mauviel, Alain
影响因子：
20.3
作者：
Hager-Theodorides, AL;Dessens, JT;Crompton, T
通讯作者：
Crompton, T
影响因子：
4.3
作者：
Agathocleous, Michalis;Locker, Morgane;Perron, Muriel
通讯作者：
Perron, Muriel
影响因子：
30.5
作者：
El Abdaloussi, E;Graves, S;Aifantis, I
通讯作者：
Aifantis, I