Gorelik L, Bar-Dagan Y, Mokyr M B
Department of Biochemistry, University of Illinois at Chicago, IL 60680, USA.
J Immunol. 1996 Jun 1;156(11):4298-308.
We have shown previously that addition of TNF to stimulation cultures of MOPC-315 tumor bearer splenic cell suspensions containing metastatic tumor cells capable of secreting TGF-beta greatly enhances the generation of anti-MOPC-315 lytic activity by their CD8+ T cells. The current studies were undertaken to gain some insight into the mechanism(s) through which TNF potentiates the in vitro generation of anti-MOPC-315 cytotoxicity by such tumor bearer splenic cells. Here we show that TNF is capable of 1) preventing completely the inhibitory activity of TGF-beta for CTL generation when both cytokines are added at the time of initiation of a 5-day stimulation culture and 2) reversing at least part of the inhibitory activity of TGF-beta when TNF is added as late as 3 days after TGF-beta addition. The costimulatory molecule B7-2 is shown here to be important for the realization of the potentiating activity of TNF for CTL generation by tumor bearer splenic cells. However, despite the importance of the B7-2 molecule, TNF does not mediate its immunopotentiating activity for CTL generation through up-regulation in IL-2 production. In addition, we show here that GM-CSF, but not IL-12, is important for the potentiating effect of TNF for CTL generation by tumor bearer splenic cells. Taken together, these studies identify several factors that are important for the realization of the potentiating effect of TNF for the in vitro generation of antitumor cytotoxicity by tumor-infiltrated splenic cells. It is not known at present, however, whether these factors utilize distinct and/or overlapping mechanisms in realizing the TNF effect.
我们之前已经表明，将肿瘤坏死因子（TNF）添加到含有能够分泌转化生长因子-β（TGF-β）的转移性肿瘤细胞的MOPC-315肿瘤荷瘤小鼠脾细胞悬液的刺激培养物中，能极大地增强其CD8⁺T细胞产生抗MOPC-315裂解活性的能力。目前的研究旨在深入了解TNF增强此类肿瘤荷瘤小鼠脾细胞体外产生抗MOPC-315细胞毒性的机制。在此我们表明，TNF能够：1）在为期5天的刺激培养开始时同时添加这两种细胞因子时，完全阻止TGF-β对细胞毒性T淋巴细胞（CTL）产生的抑制活性；2）在TGF-β添加后最晚3天添加TNF时，至少逆转TGF-β的部分抑制活性。共刺激分子B7-2对于实现TNF对肿瘤荷瘤小鼠脾细胞产生CTL的增强活性很重要。然而，尽管B7-2分子很重要，但TNF并不是通过上调白细胞介素-2（IL-2）的产生来介导其对CTL产生的免疫增强活性。此外，我们在此表明，粒细胞-巨噬细胞集落刺激因子（GM-CSF）而非白细胞介素-12（IL-12）对于TNF对肿瘤荷瘤小鼠脾细胞产生CTL的增强作用很重要。综上所述，这些研究确定了几个对于实现TNF对肿瘤浸润脾细胞体外产生抗肿瘤细胞毒性的增强作用很重要的因素。然而，目前尚不清楚这些因素在实现TNF效应时是否利用了不同和/或重叠的机制。
