Interleukin-12 is produced by dendritic cells and mediates T helper 1 development as well as interferon-gamma production by T helper 1 cells
Interleukin-12 is produced by dendritic cells and mediates T helper 1 development as well as interferon-gamma production by T helper 1 cells
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DOI：
10.1002/eji.1830260323
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发表时间：
1996-03-01
影响因子：
5.4
通讯作者：
Schuler, G
中科院分区：
文献类型：
--
作者：
Heufler, C;Koch, F;Schuler, G
白细胞介素-12（IL-12）是一种由共价连接的p35和p40链组成的70-kDa异源二聚体细胞因子，迄今为止是使免疫应答偏向细胞因子谱的T辅助细胞1（Th 1）的最关键因素[高干扰素-γ（IFN-γ），低IL-4]。IL-12的确定来源是刺激的巨噬细胞、嗜中性粒细胞和B细胞。由于树突状细胞（DC）在外周处理抗原，然后迁移到淋巴器官，使T细胞致敏并诱导细胞介导的免疫，我们推断DC应构成IL-12的关键来源。用于检测DC中IL-12的标准是p40和p35 mRNA（半定量聚合酶链反应、北方印迹和原位杂交）以及IL-12蛋白（p70酶联免疫吸附试验、p70抗原捕获随后IFN-γ生物测定、游离p40链放射免疫测定或免疫沉淀）的证明。我们发现，常规的刺激，如金黄色葡萄球菌诱导产生的IL-12，小鼠以及人类DC的数量相当的脾细胞。腹膜巨噬细胞或外周血单核细胞。然而，DC表现出与其他抗原呈递细胞没有看到的特征：在同种异体混合白细胞反应模型中，它们在与T细胞抗原特异性相互作用时产生生物活性IL-12，而无需任何其他刺激。中和抗IL-12抗体显示DC衍生的IL-12对于活化的Th 1母细胞的最佳增殖和IFN-γ产生是关键的;最后，用DC引发静息的幼稚同种异体T细胞，然后用DC再刺激引发的T母细胞，使对Th 1的应答偏斜，而不需要任何外源性细胞因子或刺激物如微生物。这种偏向于Th 1细胞因子的产生，依赖于DC衍生的IL-12，但不需要抗IL-4，外源性IL-12或微生物，可能是DC的主要功能。
Interleukin-12 (IL-12), a 70-kDa heterodimeric cytokine composed of covalently linked p35 and p40 chains, is to date the most critical factor for skewing the immune response towards a T helper 1 (Th 1) of cytokine profile [high interferon-gamma (IFN-gamma), low IL-4]. Established sources of IL-12 are stimulated macrophages, neutrophils and B cells. As dendritic cells (DC) process antigen in the periphery and then migrate to lymphoid organs to sensitize T cells and induce cell-mediated immunity, we reasoned that DC should constitute a critical source of IL-12. The criteria used to detect IL-12 in DC were the demonstration of p40 and p35 mRNA (semiquantitative polymerase chain reaction, Northern blotting, and in situ hybridization) as well as IL-12 protein (p70 enzyme-linked immunosorbent assay, p70 antigen capture followed by IFN-gamma bioassay, free p40 chain radioimmunoassay or immunoprecipitation). We found that conventional stimuli such as Staphylococcus aureus induced production of IL-12, by murine as well as human DC in amounts comparable to spleen cells. peritoneal macrophages or peripheral blood mononuclear cells. DC exhibited, however, features that had not been seen with other antigen-presenting cells: they produced bioactive IL-12 upon antigen-specific interaction with T cells without any other stimuli: in an allogeneic mixed leukocyte reaction model. neutralizing anti-IL-12 antibodies showed that DC-derived IL-12 was critical for optimal proliferation and IFN-gamma production by activated Th1 blasts; and finally, the priming of resting, naive allogeneic T cells by DC, followed by restimulation of primed T blasts by DC, skewed the response to Th1 without the need for any exogenous cytokines or stimuli such as microorganisms. This skewing to Th1 cytokine production, which depended on DC-derived IL-12, but did not require anti-IL-4, exogenous IL-12, or microbes, might be a major function of DC.