Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1674, USA.
Proc Natl Acad Sci U S A. 2010 Nov 9;107(45):19455-60. doi: 10.1073/pnas.1008271107. Epub 2010 Oct 25.
Thymic stromal lymphopoietin (TSLP) is a type I cytokine that plays essential roles in allergic/inflammatory skin and airway disorders, in helminth infections, and in regulating intestinal immunity. TSLP signals via IL-7Rα and a specific TSLPR subunit that is highly related to the common cytokine receptor γ chain, γ(c). Although TSLP has effects on a broad range of hematopoetic cells and can induce STAT5 phosphorylation, TSLP was reported to not signal via JAK kinases, and the mechanism by which TSLP regulates STAT5 phosphorylation has been unclear. We now demonstrate the role of JAK1 and JAK2 in TSLP-mediated STAT5 phosphorylation in mouse and human primary CD4(+) T cells, in contrast to the known activation of JAK1 and JAK3 by the related cytokine, IL-7. We also show that just as JAK1 interacts with IL-7Rα, JAK2 is associated with TSLPR protein. Moreover, we demonstrate the importance of STAT5 activation for TSLP-mediated survival and proliferation of CD4(+) T cells. These findings clarify the basis for TSLP-mediated signaling and provide an example wherein a cytokine uses JAK1 and JAK2 to mediate the activation of STAT5.
胸腺基质淋巴细胞生成素 (TSLP) 是一种 I 型细胞因子，在过敏性/炎症性皮肤和气道疾病、寄生虫感染以及调节肠道免疫中发挥重要作用。TSLP 通过 IL-7Rα 和一个与共同细胞因子受体 γ 链 (γ(c)) 高度相关的特定 TSLPR 亚基信号传导。尽管 TSLP 对广泛的造血细胞有影响，并能诱导 STAT5 磷酸化，但据报道 TSLP 不通过 JAK 激酶信号传导，并且 TSLP 调节 STAT5 磷酸化的机制尚不清楚。我们现在证明了 JAK1 和 JAK2 在 TSLP 介导的小鼠和人类原代 CD4(+) T 细胞中 STAT5 磷酸化中的作用，与相关细胞因子 IL-7 激活 JAK1 和 JAK3 形成对比。我们还表明，就像 JAK1 与 IL-7Rα 相互作用一样，JAK2 与 TSLPR 蛋白相关联。此外，我们证明了 STAT5 激活对于 TSLP 介导的 CD4(+) T 细胞存活和增殖的重要性。这些发现阐明了 TSLP 介导的信号传导的基础，并提供了一个例证，即细胞因子使用 JAK1 和 JAK2 来介导 STAT5 的激活。
