Phenotypic models of T cell activation

Supervised by Dr. Omer Dushek, Prof. Anton van der Merwe and Prof. Philip Maini

Unravelling the mind of the T cell

T cell activation is a crucial checkpoint in adaptive immunity, and this activation depends on the binding parameters between the T cell receptor (TCR) and peptide-MHC (pMHC) complexes as well as the dose at which the pMHC is presented. Despite extensive experimental studies, it still remains controversial as to how these parameters govern the resultant activation. Although published models of T cell activation exhibit some aspects of the experimental data, there is no model that captures the data in entirety. How is the magnitude of the T cell's response governed by the dose and affinity of peptide that it interacts with?

My work consists of developing a model that captures the phenotype of T cell activation. This model is influenced by existing models in the literature as well as a quantitative dataset we have generated that probes T cell activation over wide range of pMHC binding parameters and doses. The dataset was generated by stimulating CD8+ jurkats and primary cells transduced with a therapeutic high affinity T cell receptor with a panel of plate bound pMHC that are point mutations of the HLA-A2 NYESO pMHC. The panel of ligands have a 105-fold range in binding time for the TCR as measured by surface plasmon resonance. Activation was quantified by measuring IL8 and IFN-gamma secretion several hours after stimulation for jurkats and primary cells respectively. Interestingly, we have observed from the data that there is an optimal ligand binding time that gives the most potent activation. Of further interest is the observation of an inhibition in T cell activation at high doses of pMHC presentation. This phenomenon has been previously observed in a few examples the literature. Our results indicate that a kinetic proofreading with limited signalling mechanism combined with a negative signalling motif within the T cell can produced this observed phenotype of optimal ligand binding time and optimal ligand dose.

Publications
1. M Lever, PK Maini, PA van der Merwe, O Dushek: Phenotypic models of T cell activation. Nature Reviews Immunology.14. 619-629 (2014).
2. M Fairhead, G Veggiani, M Lever, J Yan, D Mesner, C Robinson, O Dushek, P Merwe, M Howarth: SpyAvidin Hubs Enable Precise and Ultrastable Orthogonal Nanoassembly.Journal of the American Chemical Society. 136 . 12355-12363 (2014).

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