Center for Quantitative Medicine, School of Medicine, UConn Health, 263 Farmington Ave., Farmington, CT, USA.
Department of Immunology, School of Medicine, UConn Health, 263 Farmington Ave., Farmington, CT, USA.
Sci Rep. 2019 Jul 26;9(1):10862. doi: 10.1038/s41598-019-47333-y.
Combined agonist stimulation of the TNFR costimulatory receptors 4-1BB (CD137) and OX40(CD134) has been shown to generate supereffector CD8 T cells that clonally expand to greater levels, survive longer, and produce a greater quantity of cytokines compared to T cells stimulated with an agonist of either costimulatory receptor individually. In order to understand the mechanisms for this effect, we have created a mathematical model for the activation of the CD8 T cell intracellular signaling network by mono- or dual-costimulation. We show that supereffector status is generated via downstream interacting pathways that are activated upon engagement of both receptors, and in silico simulations of the model are supported by published experimental results. The model can thus be used to identify critical molecular targets of T cell dual-costimulation in the context of cancer immunotherapy.
联合激动剂刺激 TNFR 共刺激受体 4-1BB（CD137）和 OX40（CD134）已被证明可产生超效 CD8 T 细胞，与单独用激动剂刺激任一共刺激受体相比，这些 T 细胞可更大程度地克隆扩增、更长时间存活并产生更多细胞因子。为了了解这种效应的机制，我们创建了一个数学模型来描述 CD8 T 细胞内信号网络的单或双共刺激激活。我们表明，超效状态是通过两个受体结合后激活的下游相互作用途径产生的，并且模型的计算机模拟结果得到了已发表的实验结果的支持。因此，该模型可用于确定癌症免疫治疗中 T 细胞双共刺激的关键分子靶标。
