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

Summary

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.

Graphical Abstract

Highlights

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  We construct a mathematical model to explore CAR-mediated MAPK signaling

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  Model predicts how intracellular CAR domains affect ERK response time

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  CD28 influences ERK activation by enhancing the phosphorylation kinetics of CD3ζ

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  Removing ITAMs from CD3ζ speeds up ERK response and reduces negative feedback

Abstract

Immunology; Immunology Theories; Computational Bioinformatics