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Quantifying persistence in the T-cell signaling network using an optically controllable antigen receptor.

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T cells discriminate between healthy and infected cells with remarkable sensitivity when mounting an immune response, which is hypothesized to depend on T cells combining stimuli from multiple antigen-presenting cell interactions into a more potent response. To quantify the capacity for T cells to accomplish this, we have developed an antigen receptor that is optically tunable within cell conjugates, providing control over the duration, and intensity of intracellular T-cell signaling. We observe limited persistence within the T-cell intracellular network on disruption of receptor input, with signals dissipating entirely in ~15 min, and directly show sustained proximal receptor signaling is required to maintain gene transcription. T cells thus primarily accumulate the outputs of gene expression rather than integrate discrete intracellular signals. Engineering optical control in a clinically relevant chimeric antigen receptor (CAR), we show that this limited signal persistence can be exploited to increase CAR-T cell activation threefold using pulsatile stimulation. Our results are likely to apply more generally to the signaling dynamics of other cellular networks.



T cells, cell signaling, optogenetics, receptors, transcription factors, Calcium, Cell Line, HEK293 Cells, Humans, Jurkat Cells, Lymphocyte Activation, Optogenetics, Protein Engineering, Receptors, Antigen, T-Cell, Receptors, Chimeric Antigen, Signal Transduction, T-Lymphocytes

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Mol Syst Biol

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Springer Science and Business Media LLC
Wellcome Trust (099966/Z/12/Z, 102195/Z/13/Z)
Biotechnology and Biological Sciences Research Council (BB/M017982/1)
UKRI|Biotechnology and Biological Sciences Research Council (BBSRC) (BB/M017982/1)
UKRI|Engineering and Physical Sciences Research Council (EPSRC) (EP/L016494/1)