Interleukin 12 induces stable priming for interferon gamma (IFN-gamma) production during differentiation of human T helper (Th) cells and transient IFN-gamma production in established Th2 cell clones.
Interleukin 12 induces stable priming for interferon gamma (IFN-gamma) production during differentiation of human T helper (Th) cells and transient IFN-gamma production in established Th2 cell clones.
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DOI：
10.1084/jem.179.4.1273
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发表时间：
1994-04-01
期刊：
影响因子：
--
通讯作者：
Trinchieri G
中科院分区：
文献类型：
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作者：
Manetti R;Gerosa F;Giudizi MG;Biagiotti R;Parronchi P;Piccinni MP;Sampognaro S;Maggi E;Romagnani S;Trinchieri G
白细胞介素 12 (IL-12) 促进 1 型辅助性 T (Th1) 反应的产生，并产生大量干扰素 γ (IFN-gamma)，同时抑制人和鼠 T 细胞多克隆培养物以及小鼠体内产生 IL-4 的 Th2 细胞的产生。在这项研究中，我们分析了人类 T 细胞克隆过程中存在的 IL-12 对克隆细胞因子谱的影响。所使用的培养系统允许几乎每个 T 细胞的克隆生长，因此排除了预先选定的 Th 细胞前体的选择在确定克隆特征中发挥作用的可能性。克隆过程中存在的 IL-12 赋予 CD4+ 和 CD8+ 克隆产生 IFN-γ 的能力，其水平比在不存在 IL-12 的情况下产生的克隆中观察到的水平高几倍。这种引发是稳定的，因为当克隆在不存在 IL-12 的情况下培养 11 天时，维持了高水平的 IFN-γ 产生。 CD4+ 和一些 CD8+ 克隆产生不同量的 IL-4。与 IFN-γ 不同，IL-4 的产生在存在或不存在 IL-12 的情况下产生的克隆中没有显着差异。这些数据表明 IL-12 启动克隆祖细胞，诱导它们分化为高 IFN-γ 产生克隆。在存在 IL-12 的情况下，在体内和体外多克隆产生的 T 细胞中观察到的 IL-4 产生细胞的抑制在该克隆模型中没有观察到，这表明该抑制更多地依赖于非 IL-4 产生细胞的正选择，而不是单个克隆的分化。然而，无法用任何其他诱导剂产生IFN-γ的抗原特异性建立的Th2克隆在用IL-12与特异性抗原或不溶性抗CD3抗体组合刺激时确实产生低但显着水平的IFN-γ。这种 IFN-γ 基因表达的诱导是短暂的，因为用 IL-12 培养已建立的克隆长达 1 周，当在不存在 IL-12 的情况下进行刺激时，不会将它们转化为 IFN-γ 产生者。这些结果表明，Th 克隆对 IL-12 处理作出反应，要么稳定引发 IFN-γ 产生，要么仅短暂低水平表达 IFN-γ 基因，具体取决于它们的分化阶段。
Interleukin 12 (IL-12) facilitates the generation of a T helper type 1 (Th1) response, with high interferon gamma (IFN-gamma) production, while inhibiting the generation of IL-4-producing Th2 cells in polyclonal cultures of both human and murine T cells and in vivo in the mouse. In this study, we analyzed the effect of IL-12, present during cloning of human T cells, on the cytokine profile of the clones. The culture system used allows growth of clones from virtually every T cell, and thus excludes the possibility that selection of precommitted Th cell precursors plays a role in determining characteristics of the clones. IL-12 present during the cloning procedures endowed both CD4+ and CD8+ clones with the ability to produce IFN-gamma at levels severalfold higher than those observed in clones generated in the absence of IL-12. This priming was stable because the high levels of IFN-gamma production were maintained when the clones were cultured in the absence of IL-12 for 11 d. The CD4+ and some of the CD8+ clones produced variable amounts of IL-4. Unlike IFN-gamma, IL-4 production was not significantly different in clones generated in the presence or absence of IL-12. These data suggest that IL-12 primes the clone progenitors, inducing their differentiation to high IFN-gamma-producing clones. The suppression of IL-4-producing cells observed in polyclonally generated T cells in vivo and in vitro in the presence of IL-12 is not observed in this clonal model, suggesting that the suppression depends more on positive selection of non-IL-4-producing cells than on differentiation of individual clones. However, antigen- specific established Th2 clones that were unable to produce IFN-gamma with any other inducer did produce IFN-gamma at low but significant levels when stimulated with IL-12 in combination with specific antigen or insoluble anti-CD3 antibodies. This induction of IFN-gamma gene expression was transient, because culture of the established clones with IL-12 for up to 1 wk did not convert them into IFN-gamma producers when stimulated in the absence of IL-12. These results suggest that Th clones respond to IL-12 treatment either with a stable priming for IFN- gamma production or with only a transient low level expression of the IFN-gamma gene, depending on their stage of differentiation.