van de Wetering Diederik, de Paus Roelof A, van Dissel Jaap T, van de Vosse Esther
Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
Int Immunol. 2009 Feb;21(2):145-53. doi: 10.1093/intimm/dxn132. Epub 2008 Dec 15.
NK and NK-like T cells play an essential role in linking innate and adaptive immunity through their ability to secrete IFN-gamma. The exact trigger initiating production of IFN-gamma is uncertain. Antigen-presenting cell (APC)-derived IL-12 is thought to be the classical IFN-gamma-inducing cytokine but requires an additional stimulus such as IFN-gamma itself. IL-23 and IL-18 are among the first cytokines secreted by APC in response to binding of pathogen-associated molecular patterns such as LPS. Thus, early APC-derived IL-23 may be an initial trigger of IFN-gamma production in NK and NK-like T cells. Herein, we characterized the effect of IL-23 on IFN-gamma secretion by NK and NK-like T cells. Our findings show that IL-23 and IL-18 synergistically elicit IFN-gamma production in NK-like T cells but not in NK cells. In contrast, IL-12 together with IL-18-induced secretion of IFN-gamma in both populations. The observed synergy between IL-23 and IL-18 in NK-like T cells coincided with IL-23-mediated up-regulation of IL-18Ralpha. Furthermore, IL-23 up-regulated CD56 expression in NK-like T cells and, together with IL-18, induced proliferation of NK and NK-like T cells. We postulate a role for APC-derived IL-23 in the activation of NK and NK-like T cells early in infection and in shaping T(h)1 differentiation, via induction of IFN-gamma, which provides the additional stimulus needed for APC to subsequently produce IL-12.
自然杀伤细胞（NK）和NK样T细胞通过分泌γ干扰素的能力，在连接先天性免疫和适应性免疫方面发挥着重要作用。引发γ干扰素产生的确切触发因素尚不确定。抗原呈递细胞（APC）来源的白细胞介素-12（IL-12）被认为是经典的γ干扰素诱导细胞因子，但需要诸如γ干扰素本身等额外刺激。IL-23和IL-18是APC在响应病原体相关分子模式（如脂多糖）结合时最早分泌的细胞因子之一。因此，早期APC来源的IL-23可能是NK和NK样T细胞中γ干扰素产生的初始触发因素。在此，我们描述了IL-23对NK和NK样T细胞分泌γ干扰素的影响。我们的研究结果表明，IL-23和IL-18协同诱导NK样T细胞而非NK细胞产生γ干扰素。相比之下，IL-12与IL-18共同诱导这两种细胞群体分泌γ干扰素。在NK样T细胞中观察到的IL-23和IL-18之间的协同作用与IL-23介导的IL-18Rα上调相一致。此外，IL-23上调了NK样T细胞中CD56的表达，并与IL-18一起诱导NK和NK样T细胞增殖。我们推测，APC来源的IL-23在感染早期激活NK和NK样T细胞以及通过诱导γ干扰素来塑造辅助性T细胞1（Th1）分化方面发挥作用，γ干扰素为APC随后产生IL-12提供了所需的额外刺激。
