Regulation of JAK/STAT pathways in the eye

在这项研究中，我们第一次表明，典型的Th 17转录因子，STAT 3，与O类叉头转录因子合作，通过上调O类叉头转录因子限制过度T细胞增殖，赋予Th 17表型生存优势。与瞬时产生大量IL-2的Th 1细胞相反，我们表明Th 17细胞组成性产生较低水平的IL-2。通过将IL-2产生限制在非常低的水平，Th 17细胞避免引起IL-2诱导的活化诱导的细胞死亡，同时促进Th 17稳态扩增。低组成性IL-2表达还赋予低IL-2环境中的选择性生长优势，这允许Th 17效应细胞存活并持续存在于外周组织中，并促进慢性炎症，如葡萄膜炎。此外，我们发现STAT 3在所有T细胞中具有广泛的功能，并且它是调节淋巴细胞静止和控制T细胞活化和存活的机制的汇聚点。我们还提供了关于STAT 3和Forkhead转录因子如何收敛以对所有淋巴细胞亚群进行全局调节的机制见解。具体来说，我们表明：（i）STAT 3通过上调T细胞静止因子的表达来抑制T细胞增殖（FoxO 1，FoxO 3a，Foxj 1）和p27 Kip 1;（ii）虽然STAT 3主要作为转录因子发挥作用，但我们发现它通过一种新的转录非依赖性机制抑制辅助性T细胞的扩增，其中STAT 3与细胞质中的FoxO 1/Foxo 3a相互作用，诱导其响应于IL-6刺激的核定位，并通过促进κIB介导的NF- B隔离κ来减少IL-2的产生;（iii）STAT 3通过上调抗凋亡Bcl-2和OX 40同时下调促凋亡蛋白来促进淋巴细胞存活。就更广泛的生物学意义而言，重要的是要注意FoxO蛋白参与调节C.优雅因此，与它们在蠕虫中的作用类似，FoxO和STAT 3通路会聚以延长淋巴细胞的寿命。

In this study we show for the first time that the quintessential Th17 transcription-factor, STAT3, collaborates with Class-O Forkhead transcription-factors to confer survival advantages to Th17 phenotype by limiting excessive T cell proliferation through upregulation of Class O Forkhead transcription factors. In contrast to Th1 cells that transiently produce high amounts of IL-2, we show that Th17 cells constitutively produce lower levels of IL-2. By limiting IL-2 production to very low levels, the Th17 cells avoid provoking IL-2-induced activation-induced-cell-death while promoting Th17 homeostatic expansion. Low constitutive IL-2 expression also confers selective growth advantage in low IL-2 environment and this allows Th17 effector cells to survive and persist in peripheral tissues and promote chronic inflammation, such as uveitis. In addition, we found that STAT3 has wide-ranging functions in all T cells and that it is convergence point for mechanisms that regulate lymphocyte quiescence and those controlling T cell activation and survival. We also provide mechanistic insights into how STAT3 and Forkhead transcription-factors converge to exert global regulation on all lymphocyte subsets. Specifically we show that: (i) STAT3 inhibits T-cell proliferation by up-regulating expression of T-cell quiescence factors (FoxO1, FoxO3a, Foxj1) and p27Kip1; (ii) Although STAT3 functions mainly as a transcription-factor, we show that it inhibits expansion of T-helper cells through a novel transcription-independent mechanism whereby STAT3 interacted with FoxO1/Foxo3a in cytoplasm, induced their nuclear localization in response to IL-6-stimulation and curtailed IL-2 production by promoting IκB-mediated sequestration of NF-κB; (iii) STAT3 promoted lymphocyte survival by up-regulating anti-apoptotic Bcl-2 and OX40 while down-regulating pro-apoptotic proteins. In terms of broader biological significance, it is important to note that FoxO proteins are implicated in regulating lifespan of C. elegans. Thus similar to their role in worms, FoxO and STAT3 pathways converge to extend lifespan of lymphoid cells.