Yoshizawa H, Chang A E, Shu S Y
Department of Surgery, University of Michigan, Ann Arbor 48109.
Cancer Res. 1992 Mar 1;52(5):1129-36.
Previous studies have demonstrated that progressive growth of the weakly immunogenic MCA 106 murine sarcoma stimulated, in the draining lymph nodes, the production of tumor-sensitized but not fully functional preeffector lymphocytes. These lymphocytes could develop into specific immune effector cells after sequential in vitro activation with anti-CD3 monoclonal antibody and interleukin 2 (IL-2). In this study, we analyzed cellular requirements for in vivo sensitization of preeffector cells, for generation of immune effector cells by the method of anti-CD3/IL-2 activation, and for adoptive immunotherapy mediated by activated cells. By selective depletion of T-cell subsets in vivo, we found that tumor regression after systemic adoptive immunotherapy required the collaboration of activated CD4+ and CD8+ cells. It was further demonstrated that CD8+ immune cells alone could mediate antitumor effects if exogenous IL-2 was provided in vivo. These results suggest that CD8+ cells served as immediate effector cells, whereas CD4+ immune cells provided a helper function via the secretion of IL-2. During in vitro anti-CD3/IL-2 activation, generation of effector cells depended on the collaborative interaction between previously sensitized CD4+ and CD8+ preeffector cells. At the stage of in vitro activation, the addition of IL-2 could not substitute the function of CD4+ cells. We next examined whether the sensitization of preeffector cells in the draining lymph nodes required cellular interactions between CD4+ and CD8+ T-cells. By in vivo depletion of T-cell subsets during tumor growth, we found that CD4+ cells were sensitized independently of CD8+ cells. More interestingly, in vivo sensitization of CD8+ preeffector cells also occurred independently in the absence of a CD4+ helper cell response. The lack of T-cell-T-cell interactions in vivo may explain the failure of effector cell generation during progressive tumor growth. Taken together, these results demonstrate that the anti-CD3/IL-2 activation defines an immune response distinct from many previously described mechanisms of antitumor immune responses.
先前的研究表明，弱免疫原性的MCA 106小鼠肉瘤的渐进性生长在引流淋巴结中刺激产生了肿瘤致敏但功能未完全成熟的前效应淋巴细胞。这些淋巴细胞在用抗CD3单克隆抗体和白细胞介素2（IL-2）进行体外顺序激活后可发育成特异性免疫效应细胞。在本研究中，我们分析了前效应细胞体内致敏、通过抗CD3/IL-2激活方法产生免疫效应细胞以及活化细胞介导的过继性免疫治疗的细胞需求。通过体内选择性清除T细胞亚群，我们发现全身过继性免疫治疗后的肿瘤消退需要活化的CD4+和CD8+细胞的协作。进一步证明，如果体内提供外源性IL-2，单独的CD8+免疫细胞即可介导抗肿瘤作用。这些结果表明，CD8+细胞作为直接效应细胞，而CD4+免疫细胞通过分泌IL-2发挥辅助功能。在体外抗CD3/IL-2激活过程中，效应细胞的产生依赖于先前致敏的CD4+和CD8+前效应细胞之间的协作相互作用。在体外激活阶段，添加IL-2不能替代CD4+细胞的功能。接下来，我们研究了引流淋巴结中前效应细胞的致敏是否需要CD4+和CD8+ T细胞之间的细胞相互作用。通过在肿瘤生长期间体内清除T细胞亚群，我们发现CD4+细胞的致敏独立于CD8+细胞。更有趣的是，在没有CD4+辅助细胞反应的情况下，CD8+前效应细胞的体内致敏也独立发生。体内T细胞 - T细胞相互作用的缺乏可能解释了在肿瘤进行性生长过程中效应细胞产生失败的原因。综上所述，这些结果表明，抗CD3/IL-2激活定义了一种与许多先前描述的抗肿瘤免疫反应机制不同的免疫反应。
