We have a near-complete characterisation of the components for many biological signalling networks, but their dynamic interconnections remain poorly understood. Current methods to investigate intracellular signalling generally disrupt one point in the network and compare cell function afterwards. However, the intervention can never be made without perturbing the rest of the system and rarely provides the dynamic information required for a mechanistic understanding of network function.
Our strategy to investigate cell signalling is to provide quantitative and dynamic inputs to the intact network, measure the corresponding functional outputs and then infer characteristics of the underlying system. To achieve the required spatio-temporal control over signalling, we develop light-controlled biological components that enable us to modulate both the intensity and frequency of signalling within the network.
We currently focus on the intracellular signalling of T cells, an essential immune cell-type that detect infected cells and orchestrate their removal. Using our new tools, our key goal is to provide a quantitative understanding of how different T cell inputs are decoded by the dynamics of the signalling pathways to specify the appropriate response. Through this, we hope to discover parts of the network that could be fine-tuned therapeutically to alleviate diseases when T cell function becomes deleterious.
James, J.R. (2018) Tuning ITAM multiplicity on T cell receptors can control potency and selectivity to ligand density. Sci Signal. 11(531). doi:10.1126/scisignal.aan1088
Liaunardy-Jopeace, A., Murton, B.L., Mahesh, M., Chin, J.W., James, J.R. (2017) Encoding optical control in LCK kinase to quantitatively investigate its activity in live cells. Nat Struct Mol Biol. 24(12). doi:10.1038/nsmb.3492
Li, J., Stagg, N.J., Johnston, J., Harris, M.J., Menzies, S.A., […] James, J.R., Junttila, T.T. (2017) Membrane-Proximal Epitope Facilitates Efficient T Cell Synapse Formation by Anti-FcRH5/CD3 and Is a Requirement for Myeloma Cell Killing. Cancer Cell. 31(3). doi:10.1016/j.ccell.2017.02.001
James, J.R., Vale, R.D. (2012) Biophysical mechanism of T-cell receptor triggering in a reconstituted system. Nature. 487(7405). doi:10.1038/nature11220