Abstract

In the past we identified what turned out to be the complete set of T cell-specific proteins expressed at the resting T-cell surface and showed how, for key examples, they interact with their ligands. We also proposed, with P.A. van der Merwe, a counter-intuitive explanation for how key receptors are “triggered” by their ligands, now known as the “kinetic-segregation” model.

Our present research is extending these analyses of the functions and behaviour of leukocyte receptors. We have an experimental framework for testing the kinetic-segregation model at the level at which it is proposed to operate, i.e. the single-molecule level. We have also established methods for the quantitative treatment of bioluminescence resonance energy transfer data that we are using to establish the organizational “ground-state” of the T-cell surface. We also plan to reconstitute the triggering apparatus of the T cell in insect cells in order to identify the minimum set of molecules required for triggering.

We have undertaken the very deep analysis of the CD4 + T-cell transcriptome and are using this for whole-cell level simulations of the earliest post-triggering event in signal transduction, i.e. the recruitment of SH2 domains to triggered, tyrosine-phosphorylated receptors. Finally, we are applying our understanding of the triggering process to the development of inhibitory antibody superagonists as a potential general strategy for the treatment of common autoimmune diseases. We hope to obtain proof-of-concept for the therapeutic principle following the generation of a novel “knock-in” mouse model of human autoimmunity.