PRODUCTION OF INTERLEUKIN-2 AND INTERLEUKIN-4 BY IMMUNE CD4-CD8+ AND THEIR ROLE IN THE GENERATION OF ANTIGEN-SPECIFIC CYTOTOXIC T-CELLS
PRODUCTION OF INTERLEUKIN-2 AND INTERLEUKIN-4 BY IMMUNE CD4-CD8+ AND THEIR ROLE IN THE GENERATION OF ANTIGEN-SPECIFIC CYTOTOXIC T-CELLS
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DOI：
10.1002/eji.1830210813
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发表时间：
1991-08-01
影响因子：
5.4
通讯作者：
FLOOD, PM
中科院分区：
文献类型：
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作者：
HORVAT, B;LOUKIDES, JA;FLOOD, PM
在本报告中，我们研究了白细胞介素（IL）-2和IL - 4在抗原特异性细胞毒性T细胞（CTL）产生过程中的产生情况及其作用。我们以紫外线诱导的上皮肿瘤1591作为模型，这是一种高度免疫原性的消退性肿瘤，它能引发强烈的细胞介导的免疫反应从而导致肿瘤排斥。我们发现，在体外脾细胞原代和二次培养中，针对1591肿瘤产生最佳的细胞溶解活性对IL - 2和IL - 4的需求存在差异。首先，抗IL - 2受体单克隆抗体（mAb）在脾细胞原代和二次混合淋巴细胞 - 肿瘤细胞培养（MLTC）中均显著降低了特异性细胞毒性，但抗IL - 4 mAb仅抑制二次培养中的细胞毒性反应，而不抑制原代培养中的反应。其次，当对MLTC的上清液进行淋巴因子活性检测时，原代培养仅产生IL - 2，而二次培养既产生IL - 2又产生IL - 4。然后通过阴性选择去除脾细胞中的CD4⁺细胞，或通过阳性选择富集CD8⁺细胞，并对其淋巴因子产生情况及需求进行检测。CD8⁺细胞在原代培养中无法产生显著的CTL活性，但在二次MLTC中可以。在这些二次MLTC中，向IL - 2或IL - 4中添加mAb均显著抑制了CD8⁺细胞产生CTL。通过功能分析和Northern杂交分析还发现，CD8⁺细胞在二次MLTC中既能产生IL - 2又能产生IL - 4。CD8⁺细胞产生IL - 2和IL - 4发生在培养的不同阶段，IL - 2产生较早（第1天和第2天），IL - 4产生较晚（第3 - 5天）。此外，CD8⁺细胞对IL - 2和IL - 4的需求对于每种淋巴因子是独特的。这些结果表明，在二次MLTC过程中，CD8⁺细胞既能产生IL - 2和IL - 4，又需要这两种因子，并且提示在抗原特异性CTL反应过程中，除了CD4⁺T细胞外，还存在产生IL - 4的其他细胞来源。
In this report we investigated the production and role of interleukin (IL)2 and IL4 in the generation of antigen-specific cytotoxic T cells (CTL). We used as our model the ultraviolet-light-induced epithelial tumor 1591, a highly immunogenic regressor tumor which evokes a strong cell-mediated immune response leading to rejection. We show that IL2 and IL4 are differentially required for the development of optimal cytolytic activity to the 1591 tumor in primary and secondary in vitro splenic cultures. First, anti-IL2 receptor monoclonal antibody (mAb) significantly decreased specific cytotoxicity in both primary and secondary splenic mixed lymphocyte-tumor cell culture (MLTC) cultures, but anti-IL4 mAb inhibited the cytotoxic responses only secondary and not primary cultures. Second, when supernatants from MLTC were tested for lymphokine activity, primary cultures produced only IL2 while secondary cultures produced both IL2 and IL4. Splenic cells were then depleted of CD4+ cells by negative selection, or enriched for CD8+ cells by positive selection, and tested for lymphokine production and requirements. CD8+ cells could not generate significant CTL activity in primary cultures, but could in secondary MLTC. The addition of mAb to either IL2 or IL4 significantly inhibited the generation of CTL by CD8+ cells in these secondary MLTC. CD8+ cells were also found to produce both IL2 and IL4 in secondary MLTC by functional and Northern blot analysis. The production of IL2 and IL4 by CD8+ cells occurs during different phases of culture, with IL2 being produced early (days 1 and 2) and IL4 late (days 3-5). In addition, the requirement of CD8+ cells for both IL2 and IL4 is unique for that lymphokine. These results suggest that both IL2 and IL4 are both produced and required by CD8+ cells during secondary MLTC, and suggest an additional cellular source of IL4 production besides CD4+ T cells during antigen-specific CTL responses.