Rubin Bent, Riond Joëlle, Courtiade Laetitia, Roullet Nicolas, Gairin Jean-Edouard
Institut de Sciences et Technologies du Médicament de Toulouse, UMR-2587, CNRS-Pierre Fabre, Toulouse, France.
Cancer Immun. 2008 Sep 11;8:14.
Tumor cells and the immune system play a lethal "pas de deux" during tumor development. However, it is not clear which role the innate immune system plays in these interactions. We studied the interaction of normal spleen cells (NSCs) with tumor cells expressing low levels of MHCI on the cell surface. This interaction induces increased MHCI expression on the MHCI(low) tumor cells by a cell-cell contact-dependent, IFN-gamma-mediated mechanism. The effector cells responsible for the increased IFN-gamma production were identified as CD4+ CD1d-independent NKT cells, NK1.1+ NK cells and CD4+ CD11c+ DCs. The possible three cell collaboration is not activated by MHCI(high) tumor cells or normal fibroblasts. Kinetic experiments showed that the increase in IFN-gamma production induced by MHCI(low) tumor cells happens in two consecutive waves, an early peak around 12 hours, followed by a second more important peak around day 2-3. Thus, we propose that CD4+ CD1d-independent NKT cells are activated by the MHCI(low) tumor cells, they release IFN-gamma stimulating DCs to produce IL-12, which in turn activates NK cells to produce large amounts of IFN-gamma. The recognition mechanism used by the CD4+ CD1d-independent non-classical NKT cells is unknown. Monoclonal antibody (mAb) blocking experiments using antibodies against either activating or inhibitory receptors or co-receptors on NKT/NK cells gave no conclusive results. Moreover, NSCs from either normal or MHCII(-/-) mice augmented MHCI expression on MHCI(low) tumors, excluding a significant role of CD4-MHCII interactions in the system. Hence the initial recognition mechanism in this system still awaits further experimentation.
在肿瘤发展过程中，肿瘤细胞与免疫系统上演着致命的“双人舞”。然而，尚不清楚先天免疫系统在这些相互作用中扮演何种角色。我们研究了正常脾细胞（NSCs）与细胞表面低水平表达MHCI的肿瘤细胞之间的相互作用。这种相互作用通过细胞间接触依赖、IFN-γ介导的机制诱导MHCI（低）肿瘤细胞上的MHCI表达增加。负责增加IFN-γ产生的效应细胞被鉴定为CD4 + CD1d非依赖性NKT细胞、NK1.1 + NK细胞和CD4 + CD11c + DCs。这种可能的三细胞协作不会被MHCI（高）肿瘤细胞或正常成纤维细胞激活。动力学实验表明，MHCI（低）肿瘤细胞诱导的IFN-γ产生增加呈连续两个波峰，早期峰值在12小时左右，随后在第2 - 3天出现第二个更重要的峰值。因此，我们提出CD4 + CD1d非依赖性NKT细胞被MHCI（低）肿瘤细胞激活，它们释放IFN-γ刺激DCs产生IL-12，进而激活NK细胞产生大量IFN-γ。CD4 + CD1d非依赖性非经典NKT细胞所使用的识别机制尚不清楚。使用针对NKT/NK细胞上激活或抑制性受体或共受体的抗体进行的单克隆抗体（mAb）阻断实验没有得出确凿结果。此外，来自正常或MHCII（-/-）小鼠的NSCs均可增强MHCI（低）肿瘤上的MHCI表达，排除了CD4 - MHCII相互作用在该系统中的重要作用。因此，该系统中的初始识别机制仍有待进一步实验研究。
