![]() ![]() ![]() It is clear that T cells require this secondary signaling through a co-stimulatory receptor, but the mechanisms through which co-stimulatory domains influence T cell activation are not clear ( Bretscher, 1999). These signaling domains are derived from endogenous T cells and typically include CD3ζ, a part of the endogenous T cell receptor (TCR), and a co-stimulatory domain, such as CD28. ![]() To better engineer CAR T cells to fight cancer, we need to improve our understanding of how these modified receptors activate T cells.ĬARs typically include an extracellular antibody-derived binding domain linked to a transmembrane domain and a number of different intracellular signaling domains ( Sadelain et al., 2013). Unfortunately, it has been difficult to extend CAR T cell therapies beyond hematological malignancies to other types of cancer, specifically solid tumors ( Morgan et al., 2010). 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.Ĭhimeric antigen receptor (CAR)-engineered T cells have been approved for the treatment of CD19+ cell malignancies ( Mullard, 2017). Comparing these model simulations with experimental data indicates that CD28 primarily influences ERK activation by enhancing the phosphorylation kinetics of CD3ζ. We performed a systematic analysis to explore the different mechanisms of CD28 co-stimulation on the ERK response time. 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. Understanding the mechanisms by which co-stimulatory domains influence signaling can help guide the design of next-generation CARs. 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. Chimeric antigen receptors (CARs) are engineered receptors that mediate T cell activation. ![]()
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