Activation of Human Natural Killer Cell Function

在完成了我们在2013财年的几个目标后，这个项目有了一个新的方向。我们正在定义NK细胞增殖激活的最低要求，使用在以前的项目中成功的方法。白细胞介素15 （IL-15）对NK细胞的存活和增殖至关重要。与其他可溶解的细胞因子不同，IL-15与IL-15受体（IL-15R）的α链结合。il - 15rα -IL-15复合物不在NK细胞上表达，但在其他细胞上表达，它们将IL-15反提呈到NK细胞上表达的IL-15R的β链和γ链上。然后，IL-15Rbeta/ γ复合物将信号传递给NK细胞，用于存活、增殖和转录一组特定基因。IL-15在免疫突触中的递呈开启了NK细胞增殖信号可能受到其他受体-配体相互作用调节的可能性。利用转染了IL-15Ralpha的昆虫细胞，无论是单独还是与其他NK受体的配体结合，我们已经证明IL-15的转呈不依赖于整合素的粘附，也不依赖于其他激活受体的信号传导。il - 15r - α链也在人类细胞系上与作为抑制受体配体的HLA I类分子结合表达。该系统模拟了人类细胞在HLA I类分子背景下发生的IL-15转呈。我们已经证明，由IL-15递呈诱导的NK细胞的增殖是由抑制受体的同时参与调节的。抑制发生在促进增殖的信号水平，但转录依赖stat5的信号不受影响。

After completion of several of our objectives in FY13, this project has taken a new direction. We are defining the minimal requirements for the activation of NK cell proliferation, using approaches that have been successful in previous projects. The interleukin 15 (IL-15) is essential for NK cell survival and proliferation. Unlike other cytokines, which are soluble, IL-15 is bound to the alpha chain of the IL-15 receptor (IL-15R). The IL-15Ralpha-IL-15 complex is not expressed on NK cells but on other cells, which trans-present IL-15 to the beta and gamma chains of the IL-15R expressed on NK cells. The IL-15Rbeta/gamma complex then transmits signals to the NK cell for survival, proliferation, and transcription of a specific set of genes. Trans-presentation of IL-15 in the context of an immunological synapse opens the possibility that signaling for NK cell proliferation may be subject to regulation by other receptor-ligand interactions. Using insect cells transfected with IL-15Ralpha, either alone or in combination with ligands for other NK receptors, we have shown that IL-15 trans-presentation occurs independently of adhesion through integrin, and of signaling by other activation receptors. The IL-15Ralpha chain was also expressed on a human cell line in combination with HLA class I molecules that serve as ligands for inhibitory receptors. This sytem mimics IL-15 trans-presentation by human cells, which occurs in the context of HLA class I molecules. We have shown that the proliferation of NK cells induced by IL-15 trans-presentation is modulated by the simultaneous engagement of inhibitory receptors. The inhibition occurs at the level of the signals that promote proliferation, but that the Stat5-dependent signals for transcription are not affected.