Chimeric antigen receptors (CARs) are engineered receptors that mediate T cell activation. CARs are comprised of activating and co-stimulatory intracellular signaling domains derived from endogenous T cells that initiate signaling required for T cell activation, including ERK activation through the MAPK pathway. Understanding the mechanisms by which co-stimulatory domains influence signaling can help guide the design of next-generation CARs. Therefore, we constructed an experimentally validated computational model of anti-CD19 CARs in T cells bearing the CD3ζ domain alone or in combination with CD28. We performed a systematic analysis to explore the different mechanisms of CD28 co-stimulation on the ERK response time. Comparing these model simulations with experimental data indicates that CD28 primarily influences ERK activation by enhancing the phosphorylation kinetics of CD3ζ. Overall, we present a mechanistic mathematical modeling framework that can be used to gain insights into the mechanism of CAR T cell activation and produce new testable hypotheses.

嵌合抗原受体（CARs）是介导T细胞活化的工程化受体。CAR由源自内源性T细胞的活化和共刺激性细胞内信号传导域组成，该域启动T细胞活化（包括通过MAPK途径的ERK活化）所需的信号传导。了解共刺激域影响信号传导的机制可以帮助指导下一代CAR的设计。因此，我们在单独带有CD3ζ结构域或与CD28结合的T细胞中构建了抗CD19 CARs的实验验证计算模型。我们进行了系统的分析，以探索CD28共同刺激ERK反应时间的不同机制。将这些模型仿真与实验数据进行比较表明，CD28主要通过增强CD3ζ的磷酸化动力学来影响ERK活化。总体而言，我们提出了一种机械数学建模框架，该框架可用于深入了解CAR T细胞激活机制并产生新的可检验的假设。