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上海士鋒生物關(guān)于調(diào)節(jié)輔助性T細(xì)胞發(fā)育靶點(diǎn)
最近更新時(shí)間：2013-6-22
提 供 商：上海士鋒生物科技有限公司資料大?。?/span>14KB
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輔助性T細(xì)胞17（T help cell 17, Th17）是一種新發(fā)現(xiàn)的CD4+輔助T細(xì)胞亞群，它能夠分泌促炎因子白細(xì)胞介素17（IL-17）。Th17細(xì)胞在機(jī)體防御反應(yīng)中具有重要的意義，除了能夠促進(jìn)清除體內(nèi)的致病微生物，同時(shí)也參與了自身免疫疾病的發(fā)生。
他們發(fā)現(xiàn)，絡(luò)氨酸磷酸酶SHP-1能夠作為一個(gè)重要的調(diào)節(jié)因子來調(diào)節(jié)Th17的發(fā)育，該調(diào)節(jié)過程利用了3個(gè)補(bǔ)充途經(jīng)。
有趣的是，通過基因敲除SHP-1，或是轉(zhuǎn)基因表達(dá)一個(gè)誘導(dǎo)的顯性負(fù)性的SHP-1，或者是用藥物抑制SHP-1的活性，都能夠強(qiáng)烈的促進(jìn)Th17的發(fā)育。
分析離體的Th17，他們發(fā)現(xiàn)在T細(xì)胞內(nèi)，利用遺傳方法或是藥物來破壞SHP-1活性會(huì)導(dǎo)致T細(xì)胞能夠強(qiáng)烈應(yīng)答于IL-6及IL-21的刺激，促進(jìn)了Th17的發(fā)育。
而且，在初始CD4+ T細(xì)胞，SHP-1能夠減少細(xì)胞因子誘導(dǎo)的STAT3的磷酸化。
總的來說，該研究表明SHP-1通過調(diào)節(jié)STAT3信號(hào)，調(diào)節(jié)了IL-6及IL-21誘導(dǎo)的Th17的發(fā)育。
The tyrosine phosphatase SHP-1 dampens murine Th17 development
Ileana S. Mauldin, Kenneth S. Tung, and Ulrike M. Lorenz.
Th17 cells represent a subset of CD4+ T helper cells that secrete the proinflammatory cytokine IL-17.Th17 cells have been ascribed both a beneficial role in promoting clearance of pathogenic fungi and bacteria, and a pathogenic role in autoimmune diseases.Here we identify the tyrosine phosphatase SHP-1 as a critical regulator of Th17 development, using 3 complementary approaches. Impaired SHP-1 activity through genetic deletion of SHP-1, transgenic expression of an inducible dominant negative SHP-1, or pharmacologic inhibition of SHP-1 strongly promotes the development of Th17.Ex vivo Th17 skewing assays demonstrate that genetic or pharmacologic disruption of SHP-1 activity in T cells results in a hyper-response to stimulation via IL-6 and IL-21, 2 cytokines that promote Th17 development.
Mechanistically, we find that SHP-1 decreases the overall cytokine-induced phosphorylation of STAT3 in primary CD4+ T cells.These data identify SHP-1 as a key modifier of IL-6–and IL-21–driven Th17 development via regulation of STAT3 signaling and suggest SHP-1 as a potential new therapeutic target for manipulating Th17 differentiation in vivo.