T-cell Biology Group
Our earliest work was focussed on understanding how cell-cell recognition proteins achieve weak, specific recognition. This involved crystallographic and mutational studies of cell adhesion molecules and co-stimulatory proteins. We also used transcriptomic approaches to identify what has since turned out to be the complete set of T cell-specific proteins expressed at the T-cell surface. This was undertaken because we felt that it was important to know how many surface proteins remained to be discovered, so that sensible and largely complete theories of cell surface function could be formulated. Having identified all the components, a major emphasis now is to understand how the proteins are organized at the resting cell surface, which is very controversial. For this we use single-molecule, fluorescence-based imaging methods developed by Professor David Klenerman at the Department of Chemistry, Cambridge University, and other approaches. We have shown that the T-cell receptor forms monovalent complexes and produced data undermining the popular notion that G protein-coupled receptors invariably dimerize.
In 1996, with PA van der Merwe, we proposed a counter-intuitive explanation for how some of the most important receptors in the immune system, including the T-cell receptor, are “triggered” by their ligands, a theory called the “kinetic-segregation” model (www.t-cellbiology.org/ks_model). We have now extended the concept to receptor triggering by “superagonistic” antibodies (www.t-cellbiology/antibody). Our present goals are (1) to show that the kinetic segregation model does indeed explain T-cell receptor triggering, and (2) to use the idea to develop new types of therapeutic antibodies. The signalling concept is being tested using structural approaches and super-resolution imaging techniques, such as dSTORM. For this, the behaviour of T-cell surface proteins is being studied at contacts with glass surfaces and supported lipid bilayers, in collaboration with Professor Klenerman. New, potentially therapeutic superagonistic antibodies are being developed and licensed to industry in collaboration with Professor Richard Cornall.