Leite-De-Moraes M C, Hameg A, Pacilio M, Koezuka Y, Taniguchi M, Van Kaer L, Schneider E, Dy M, Herbelin A
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8603, Université René Descartes, Paris V, Hôpital Necker, Paris, France.
J Immunol. 2001 Jan 15;166(2):945-51. doi: 10.4049/jimmunol.166.2.945.
NKT cells are a remarkably versatile population whose functional capacities are determined by cytokines present in their microenvironment. In this study, we provide evidence for a new immunoregulatory effect of the proinflammatory cytokine IL-18 on NKT cells. We found that IL-18, mainly known for its involvement in NK cell activation and in Th 1 immune responses, substantially enhanced IL-4 production as well as the percentage of IL-4(+) cells among NKT lymphocytes activated by their specific ligand alpha-galactosylceramide (alpha-GalCer). The effect of IL-18 on IL-4 production by activated NKT cells took place both in vivo and in vitro and was not affected by IL-12 which increased IFN-gamma secretion in the same conditions. We show that NKT cells are the main targets for IL-18-induced IL-4 production since it occurred neither in NKT-deficient mice nor after stimulation of Th2 lymphocytes. Finally, we provide evidence that the IL-4 promptly generated by NKT cells in response to IL-18 plus alpha-galactosylceramide in vivo can effectively contribute to the adaptive Th2 immune response by up-regulating the early activation marker CD69 on B cells. Our data support the notion that, in contrast to the exclusive IFN-gamma inducer IL-12, IL-18 acts in a more subtle manner as a costimulatory factor in both pro-Th1 and pro-Th2 responses depending on the nature of the stimulation and the target cells.
NKT细胞是一类功能极为多样的细胞群体，其功能能力由微环境中存在的细胞因子决定。在本研究中，我们为促炎细胞因子IL-18对NKT细胞的一种新的免疫调节作用提供了证据。我们发现，主要因其参与自然杀伤细胞激活和Th1免疫反应而闻名的IL-18，能显著增强IL-4的产生以及在其特异性配体α-半乳糖神经酰胺（α-GalCer）激活的NKT淋巴细胞中IL-4(+)细胞的百分比。IL-18对活化的NKT细胞产生IL-4的作用在体内和体外均有发生，且不受IL-12的影响，而在相同条件下IL-12会增加IFN-γ的分泌。我们表明NKT细胞是IL-18诱导IL-4产生的主要靶点，因为在NKT细胞缺陷小鼠中以及在Th2淋巴细胞刺激后均未出现这种情况。最后，我们提供证据表明，NKT细胞在体内对IL-18加α-半乳糖神经酰胺的反应中迅速产生的IL-4，可通过上调B细胞上的早期激活标志物CD69有效地促进适应性Th2免疫反应。我们的数据支持这样一种观点，即与唯一的IFN-γ诱导剂IL-12不同，IL-18作为一种共刺激因子，根据刺激的性质和靶细胞的不同，在促Th1和促Th2反应中以更微妙的方式发挥作用。
