Center for Systems Immunology, Benaroya Research Institute, Seattle, WA, 98101, USA.
Bristol-Myers Squibb, Summit, NJ, USA.
Sci Rep. 2020 Feb 5;10(1):1915. doi: 10.1038/s41598-020-58600-8.
Failure to clear antigens causes CD8 T cells to become increasingly hypo-functional, a state known as exhaustion. We combined manually extracted information from published literature with gene expression data from diverse model systems to infer a set of molecular regulatory interactions that underpin exhaustion. Topological analysis and simulation modeling of the network suggests CD8 T cells undergo 2 major transitions in state following stimulation. The time cells spend in the earlier pro-memory/proliferative (PP) state is a fixed and inherent property of the network structure. Transition to the second state is necessary for exhaustion. Combining insights from network topology analysis and simulation modeling, we predict the extent to which each node in our network drives cells towards an exhausted state. We demonstrate the utility of our approach by experimentally testing the prediction that drug-induced interference with EZH2 function increases the proportion of pro-memory/proliferative cells in the early days post-activation.
未能清除抗原会导致 CD8 T 细胞逐渐功能低下，这种状态被称为衰竭。我们结合了已发表文献中的手动提取信息和来自不同模型系统的基因表达数据，以推断出一组支持衰竭的分子调控相互作用。该网络的拓扑分析和模拟建模表明，CD8 T 细胞在刺激后会经历 2 个主要的状态转变。细胞在早期的记忆前/增殖（PP）状态中花费的时间是网络结构的固有属性。向第二个状态的转变是衰竭所必需的。结合网络拓扑分析和模拟建模的见解，我们预测了我们网络中的每个节点将细胞推向衰竭状态的程度。我们通过实验验证了我们的方法的有效性，该实验预测药物诱导的 EZH2 功能干扰会增加激活后早期记忆前/增殖细胞的比例。
