While Th17 cells can protect against colonization by pathogenic organisms, they also have the potential to become pathogenic and promote autoimmune and inflammatory diseases. Mechanisms that control their pathogenic potential remain poorly understood. Here we show that Ndfip1, a co-activator of the E3 ubiquitin ligase Itch, restricts the frequency and pathogenicity of Th17 cells. Mice lacking Ndfip1 have increased numbers of Th17 cells, and this increase is cell intrinsic. We found that Ndfip1 restricts production of the proinflammatory cytokines in Th17 cells. Increased cytokine production correlated with reduced degradation and accumulation of RORγT. When transferred in vivo, Th17 cells lacking Ndfip1 were more likely to maintain their ability to make IL-17, were more potent proinflammatory cytokine producers, and were powerful inducers of colitis. Together our data support an essential role for Ndfip1 in degrading RORγT and suppressing Th17 lineage stability, proinflammatory cytokine production, and pathogenicity.

译文

虽然Th17细胞可以防止病原生物定植,但它们也有可能成为致病性的并促进自身免疫和炎症性疾病。控制其致病潜力的机制仍然知之甚少。在这里,我们显示Ndfip1,E3泛素连接酶瘙痒的共同激活剂,限制了Th17细胞的频率和致病性。缺乏Ndfip1的小鼠Th17细胞数量增加,这种增加是细胞固有的。我们发现Ndfip1限制Th17细胞中促炎细胞因子的产生。细胞因子产生的增加与ror γ t的降解和积累减少有关。当在体内转移时,缺乏Ndfip1的Th17细胞更可能维持其制造IL-17的能力,是更有效的促炎细胞因子生产者,并且是结肠炎的强大诱导剂。我们的数据共同支持Ndfip1在降解ror γ t和抑制Th17谱系稳定性,促炎细胞因子产生和致病性方面的重要作用。

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