Journal
MOLECULAR SYSTEMS BIOLOGY
Volume 17, Issue 5, Pages -Publisher
WILEY
DOI: 10.15252/msb.202010091
Keywords
cell signaling; optogenetics; receptors; T cells; transcription factors
Categories
Funding
- Wellcome Trust [099966/Z/12/Z, 102195/Z/13/Z]
- Warwick Medical School
- University of Warwick
- EPSRC & BBSRC Centre for Doctoral Training in Synthetic Biology [EP/L016494/1]
- EPSRC
- BBSRC [BB/M017982/1]
- BBSRC [BB/M017982/1] Funding Source: UKRI
- Wellcome Trust [102195/Z/13/Z, 099966/Z/12/Z] Funding Source: Wellcome Trust
Ask authors/readers for more resources
T cells are able to distinguish between healthy and infected cells by combining stimuli from multiple antigen-presenting cell interactions. By engineering optical control in antigen receptors, it has been shown that T cells primarily accumulate gene expression outputs and this limited signal persistence can be exploited to increase CAR-T cell activation using pulsatile stimulation. These findings are likely applicable to the signaling dynamics of other cellular networks.
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 similar to 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available