A Programmed Switch from IL-15-to IL-2-Dependent Activation in Human NK Cells
A Programmed Switch from IL-15-to IL-2-Dependent Activation in Human NK Cells
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DOI：
10.4049/jimmunol.0801933
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发表时间：
2009-05-15
影响因子：
4.4
通讯作者：
Rose, Thierry
中科院分区：
文献类型：
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作者：
Pillet, Anne-Helene;Bugault, Florence;Rose, Thierry
IL-2和IL-15差异地控制人INK细胞的发育、活化和增殖，尽管它们共享共同的信号转导受体链CD 122和共同的γ。为了探讨这个问题，我们详细分析了细胞因子受体表达，细胞因子结合，和信号转导反应的动力学在人类NK细胞与常见的γ-链家族细胞因子处理。我们提供了IL-15 R α和IL-2 R α在精氨酸刺激的人NK细胞表面顺序表达的证据，与用于刺激的细胞因子（IL-2、IL-15或IL-7）无关。结合实验证实，开关的高亲和力受体从IL-15 R IL-2 R刺激后18和48小时之间。因此，在用细胞因子预处理18 h的人NK细胞中，对IL-15的磷酸化STAT 5信号传导应答是有效的，但在48 h时被消除。功能性NK细胞对IL 15的应答，包括IFN-γ分泌和CD 107 a表达，遵循类似的模式，表明细胞因子受体转换的生理相关性。重要的是，与可溶性IL-15 R α复合的IL-15保留了在48小时激活精氨酸刺激的人NK细胞的能力，表明人NK细胞仍然能够进行IL-15反式呈递，而它们对游离扩散的IL-15变得难以抵抗。这些发现定义了一种常见的细胞因子受体表达程序，该程序在早期活化中增加人INK细胞对游离IL-15的敏感性，并在后期阶段将应答重定向至IL-2和反式呈递的IL-15。这样的程序可以防止由先天免疫效应物引起的过度的人INK细胞活化，并调节免疫应答的先天和适应性阶段之间的转变，The Journal of Immunology，2009，182：6267-6277。
IL-2 and IL-15 differentially control the development, activation and proliferation of human INK cells, although they share common signal-transducing receptor chains CD122 and common gamma. To explore this issue, we analyzed in detail the kinetics of cytokine receptor expression, cytokine binding, and signaling responses in human NK cells treated with common gamma-chain family cytokines. We provide evidence for the sequential expression of IL-15R alpha and IL-2R alpha at the surface of cytokine-stimulated human NK cells, independent of the cytokine used for stimulation (IL-2, IL-15, or IL-7). Binding experiments confirmed the switch of high-affinity receptor from IL-15R to IL-2R between 18 and 48 h after stimulation. Consequently, phospho-STAT5 signaling responses to IL-15 were efficient in human NK cells pretreated with cytokines for 18 h, but were abolished at 48 h. Functional NK cell responses to IL15, including IFN-gamma secretion and CD107a expression, followed a similar pattern, indicating the physiological relevance of the cytokine receptor switch. Importantly, IL-15 complexed to soluble IL-15R alpha preserved the capacity to activate cytokine-stimulated human NK cells at 48 h, suggesting that human NK cells remained competent for IL-15 trans-presentation, while they had become refractory to free diffusible IL-15. These findings define a common cytokine receptor expression program, which increases human INK cell sensitivity to free IL-15 in early activation and redirects responses toward IL-2 and trans-presented IL-15 at later stages. Such a program may prevent excessive human INK cell activation by effectors of innate immunity and regulate the transition between the innate and adaptive stages of immune responses, The Journal of Immunology, 2009, 182: 6267-6277.