Regulation of JAK/STAT pathways in the eye

在这项研究中，我们首次发现典型的Th17转录因子STAT3与O类叉头转录因子协同作用，通过上调O类叉头转录因子来限制过度的T细胞增殖，从而赋予Th17表型生存优势。与瞬时产生大量IL-2的Th1细胞相反，我们发现Th17细胞组成性地产生较低水平的IL-2。通过将IL-2的产生限制在非常低的水平，Th17细胞避免引发IL-2诱导的活化诱导的细胞死亡，同时促进Th17的稳态扩张。低组成性IL-2表达也赋予了低IL-2环境下的选择性生长优势，这使得Th17效应细胞能够在外周组织中存活和持续存在，并促进慢性炎症，如葡萄膜炎。此外，我们发现STAT3在所有T细胞中都具有广泛的功能，并且它是调节淋巴细胞静止和控制T细胞激活和存活的机制的交汇点。我们还提供了STAT3和Forkhead转录因子如何汇聚在所有淋巴细胞亚群中发挥全局调控的机制见解。具体来说，我们发现：(i) STAT3通过上调t细胞静止因子（FoxO1、FoxO3a、Foxj1）和p27Kip1的表达来抑制t细胞增殖；（ii）尽管STAT3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独立机制抑制t辅助细胞的增殖，即STAT3与细胞质中的FoxO1/Foxo3a相互作用，诱导其核定位以响应il -6刺激，并通过促进I&#954；B介导的NF-&#954；B的隔离来减少IL-2的产生；（iii） STAT3通过上调抗凋亡Bcl-2和OX40，下调促凋亡蛋白，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蛋白与秀丽隐杆线虫的寿命调节有关。因此，类似于它们在蠕虫中的作用，FoxO和STAT3通路汇合以延长淋巴样细胞的寿命。

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.