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    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. Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.


    Jennifer A Rohrs, Elizabeth L Siegler, Pin Wang, Stacey D Finley. ERK Activation in CAR T Cells Is Amplified by CD28-Mediated Increase in CD3ζ Phosphorylation. iScience. 2020 Apr 24;23(4):101023

    PMID: 32325413

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