Schirrmacher V, Schild H J, Gückel B, von Hoegen P
Institut für Immunologie und Genetik, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Immunol Cell Biol. 1993 Aug;71 ( Pt 4):311-26. doi: 10.1038/icb.1993.36.
This study demonstrates that a syngeneic specific cytotoxic T lymphocyte (CTL) response to a class I major histocompatibility complex (MHC) positive tumour requires dual processing and recognition of tumour antigens. One type of antigen is processed and expressed in association with class I MHC at the surface of intact tumour cells. It is recognized by CD8 alpha, beta TCR CTL in vitro and by protective immune T cells in vivo and thus functions as a tumour-associated transplantation antigen (TATA). The other type of antigen is processed and expressed by distinct host APC in association with class II MHC. This is recognized by immune CD4 T cells which function as essential helper cells in the generation of the CD8 CTL response. These conclusions are supported by cell depletion and reconstitution experiments as well as by blocking experiments with monoclonal antibodies using the highly metastatic class II negative murine lymphoma ESb as a model system. The existence of two types of cognate T cell responses in a syngeneic anti-tumour response was directly proved by the establishment of two types of tumour specific T cell lines which required as co-stimulator either MHC class II positive APC or IL-2. In suboptimal mixed lymphocyte tumour cell cultures either of these co-stimulator functions was found to be limiting the overall anti-tumour CTL response. The generation of the tumour specific CTL response could be blocked by monoclonal antibodies against all the molecules involved in the cognate interactions (i.e. class I MHC, CD8, class II MHC, CD4 and TCR) but not by anti-CD2 or anti-IgG. The strict requirement for helper cells and APC could be bypassed by the addition of recombinant IL-2 but optimal triggering of CD8 CTL-precursor required viable tumour stimulator cells. This well characterized in vitro assay may be useful (i) for monitoring the immune status of CD4 and CD8 immune T cells separately, for instance of tumour bearing and/or treated animals and (ii) for the development and testing of potent tumour cell vaccines with T cell stimulatory and/or co-stimulatory activities.
本研究表明，对I类主要组织相容性复合体（MHC）阳性肿瘤的同基因特异性细胞毒性T淋巴细胞（CTL）反应需要对肿瘤抗原进行双重加工和识别。一种抗原在完整肿瘤细胞表面与I类MHC一起加工并表达。它在体外被CD8α、β TCR CTL识别，在体内被保护性免疫T细胞识别，因此作为肿瘤相关移植抗原（TATA）发挥作用。另一种抗原由不同的宿主抗原呈递细胞（APC）与II类MHC一起加工并表达。这被免疫CD4 T细胞识别，这些细胞在CD8 CTL反应的产生中作为必需的辅助细胞发挥作用。这些结论得到了细胞清除和重建实验以及使用高转移性II类阴性小鼠淋巴瘤ESb作为模型系统的单克隆抗体阻断实验的支持。通过建立两种类型的肿瘤特异性T细胞系直接证明了同基因抗肿瘤反应中存在两种类型的同源T细胞反应，这两种细胞系需要II类MHC阳性APC或IL-2作为共刺激剂。在次优混合淋巴细胞肿瘤细胞培养物中，发现这些共刺激功能中的任何一种都限制了整体抗肿瘤CTL反应。肿瘤特异性CTL反应的产生可以被针对同源相互作用中涉及的所有分子（即I类MHC、CD8、II类MHC、CD4和TCR）的单克隆抗体阻断，但不能被抗CD2或抗IgG阻断。通过添加重组IL-2可以绕过对辅助细胞和APC的严格要求，但CD8 CTL前体的最佳触发需要有活力的肿瘤刺激细胞。这种特征明确的体外测定法可能有用：（i）分别监测CD4和CD8免疫T细胞的免疫状态，例如荷瘤和/或治疗动物的免疫状态；（ii）用于开发和测试具有T细胞刺激和/或共刺激活性且有效的肿瘤细胞疫苗。
