Zhou Julie Y, Alvarez Carlos A, Cobb Brian A
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, United States.
Elife. 2021 Feb 22;10:e57417. doi: 10.7554/eLife.57417.
Cells exist within complex milieus of communicating factors, such as cytokines, that combine to generate context-specific responses, yet nearly all knowledge about the function of each cytokine and the signaling propagated downstream of their recognition is based on the response to individual cytokines. Here, we found that regulatory T cells (Tregs) integrate concurrent signaling initiated by IL-2 and IL-4 to generate a response divergent from the sum of the two pathways in isolation. IL-4 stimulation of STAT6 phosphorylation was blocked by IL-2, while IL-2 and IL-4 synergized to enhance STAT5 phosphorylation, IL-10 production, and the selective proliferation of IL-10-producing Tregs, leading to increased inhibition of conventional T cell activation and the reversal of asthma and multiple sclerosis in mice. These data define a mechanism of combinatorial cytokine signaling and lay the foundation upon which to better understand the origins of cytokine pleiotropy while informing improved the clinical use of cytokines.
细胞存在于由细胞因子等相互作用因子构成的复杂环境中，这些因子共同作用产生特定背景下的反应，但几乎所有关于每种细胞因子功能及其识别后下游信号传导的知识都基于对单个细胞因子的反应。在此，我们发现调节性T细胞（Tregs）整合由白细胞介素-2（IL-2）和白细胞介素-4（IL-4）引发的同步信号，以产生不同于两条途径单独作用之和的反应。IL-2可阻断IL-4刺激的信号转导和转录激活因子6（STAT6）磷酸化，而IL-2和IL-4协同增强信号转导和转录激活因子5（STAT5）磷酸化、白细胞介素-10（IL-10）产生以及产生IL-10的Tregs的选择性增殖，从而增强对传统T细胞激活的抑制，并逆转小鼠的哮喘和多发性硬化症。这些数据定义了一种组合细胞因子信号传导机制，为更好地理解细胞因子多效性的起源奠定了基础，同时为改善细胞因子的临床应用提供了依据。
