ERK Activation in CAR T Cells Is Amplified by CD28-Mediated Increase in CD3ζ Phosphorylation

Jennifer A Rohrs; Elizabeth L Siegler; Pin Wang; Stacey D Finley

doi:10.1016/j.isci.2020.101023

ERK Activation in CAR T Cells Is Amplified by CD28-Mediated Increase in CD3ζ Phosphorylation

iScience. 2020 Apr 24;23(4):101023. doi: 10.1016/j.isci.2020.101023. Epub 2020 Mar 30.

Authors

Jennifer A Rohrs¹, Elizabeth L Siegler², Pin Wang³, Stacey D Finley⁴

Affiliations

¹ Vir Biotechnology, Inc., San Francisco, CA 94158, USA.
² Department of Hematology, Mayo Clinic, Rochester, MN 55902,USA.
³ Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA; Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA; Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA.
⁴ Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA; Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA; Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: sfinley@usc.edu.

Abstract

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.

Keywords: Computational Bioinformatics; Immunology; Immunology Theories.

Abstract

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