Cellular and molecular mechanisms of the IL-12-induced increase in allospecific murine cytolytic T cell activity. Implications for the age-related decline in CTL.
Cellular and molecular mechanisms of the IL-12-induced increase in allospecific murine cytolytic T cell activity. Implications for the age-related decline in CTL.
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DOI：
10.4049/jimmunol.152.9.4242
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发表时间：
1994-05
影响因子：
4.4
通讯作者：
E. Bloom;J. Horváth
中科院分区：
文献类型：
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作者：
E. Bloom;J. Horváth
使用同种异体细胞刺激的原代 CTL 评估了 IL-12 增强 CTL 生成的机制以及 IL-12 改变与年龄相关的 CTL 活性下降的潜力。 2 U/ml 的 IL-12 将年轻成年小鼠中同种异体特异性 CTL 反应的产生增强了 1.5 至 5 倍，并且用低至 0.1 U/ml IL-12 即可实现并维持最佳增强效果。与MHC非限制性裂解活性的增强相比，当在5天培养期接近结束时添加IL-12时最有效，而当在收获前1至5天添加IL-12时，诱导了几乎相同的Ag特异性CTL的增强。 IL-12 对 CTL 的增强与 [3H]TdR 掺入的增加无关。 IL-12 不需要增加 IFN-γ 的产生来增强 CTL 活性，因为当 MLC 中分别包含三种不同的针对小鼠 IFN-γ 的抗体，其浓度可消除可恢复的 IFN-γ 蛋白时，它们不会抑制 IL-12 效应，但在某些条件下，会进一步增加 CTL 活性。 IL-2 抗体也不会改变 IL-12 的作用。在刺激前去除响应群体中的 ASGM1+ 细胞并没有显着改变对 IL-12 的响应。然而，刺激后获得的效应细胞中 CD8+ T 细胞的耗尽显着降低了 IL-12 诱导的 CTL 增强。因此，结果表明，IL-12 主要通过对 T 细胞的影响来增强 CTL 活性，并且这种增强与穿孔素水平大约加倍有关，而这并不是由 CD8+ 细胞比例显着增加引起的。最后，IL-12 可有效缓解与年龄相关的 CTL 活性下降，表明 IL-12 具有潜在的免疫调节作用。
The mechanism(s) by which IL-12 augments CTL generation and the potential for IL-12 to alter the age-related decline in CTL activity were assessed using primary CTL stimulated by allogeneic cells. IL-12 at 2 U/ml enhanced the generation of allospecific CTL response in young adult mice by 1.5- to 5-fold, and optimal augmentation was achieved and maintained with as low as 0.1 U/ml IL-12. In contrast to the enhancement of MHC-unrestricted lytic activity, which was most efficient when IL-12 was added near the end of the 5 day culture period, nearly equivalent augmentation of Ag-specific CTL was induced when IL-12 was added from 1 to 5 days before harvest. The augmentation of CTL by IL-12 was not associated with increased incorporation of [3H]TdR. Increased IFN-gamma production was not required for IL-12 to augment CTL activity because when three different Abs against mouse IFN-gamma were each included in the MLC at concentrations abolishing recoverable IFN-gamma protein, they did not inhibit the IL-12 effect but, under some conditions, further increased CTL activity. Ab to IL-2 also did not alter the IL-12 effect. Depletion of ASGM1+ cells from the responding population before stimulation did not significantly alter the response to IL-12. However, depletion of CD8+ T cells from effector cells obtained after stimulation substantially reduced the IL-12-induced augmentation of CTL. Thus, the results suggested that IL-12 augments CTL activity primarily through an effect on T cells, and the augmentation was associated with an approximate doubling of perforin levels, which was not caused by a significantly increased proportion of CD8+ cells. Finally, IL-12 was effective for moderating the age-related decrease in CTL activity, suggesting a potential role for immunomodulation by IL-12.