Blood：发现调节辅助性Th17细胞发育的靶点

近日，来自美国弗吉尼亚大学的研究人员发现，络氨酸磷酸酶SHP-1能够抑制Th17细胞的发育。他们表示，SHP-1也许能够成为一个新的治疗靶点来控制体内Th17的发育。

辅助性T细胞17(T help cell 17, Th17)是一种新发现的CD4+辅助T细胞亚群，它能够分泌促炎因子白细胞介素17（IL-17）。Th17细胞在机体防御反应中具有重要的意义，除了能够促进清除体内的致病微生物，同时也参与了自身免疫疾病的发生。

他们发现，络氨酸磷酸酶SHP-1能够作为一个重要的调节因子来调节Th17的发育，该调节过程利用了3个补充途经。

有趣的是，通过基因敲除SHP-1，或是转基因表达一个诱导的显性负性的SHP-1，或者是用药物抑制SHP-1的活性，都能够强烈的促进Th17的发育。

分析离体的Th17，他们发现在T细胞内，利用遗传方法或是药物来破坏SHP-1活性会导致T细胞能够强烈应答于IL-6及IL-21的刺激，促进了Th17的发育。

而且，在初始CD4+ T细胞，SHP-1能够减少细胞因子诱导的STAT3的磷酸化。

总的来说，该研究表明SHP-1通过调节STAT3信号，调节了IL-6及IL-21诱导的Th17的发育。

doi: 10.1182/blood-2011-09-377069
PMC:
PMID:

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.