Decision-making by lymphocytes (360G-Wellcome-207547_Z_17_Z)

It was recognized sixty years ago that a "trigger mechanism" must initiate immune responses. Today, however, not even the broad features of the mechanism are fully agreed, despite its intrinsic scientific interest and the remarkable clinical utility of modulating lymphocyte behaviour. We do know, however, that it encompasses two separate events: receptor triggering per se, and the integration of multiple triggering outputs. Breakthrough developments in fluorescence imaging mean that we can now study molecular behaviour at cell-cell interfaces at single-molecule resolution, in real time. This means that we can directly test whether TCR triggering is explained by a theory relying on the local, physical exclusion of phosphatases from sites of receptor engagement and phosphorylation, called the kinetic-segregation model. We will explore how 'close-contact' formation affects the interplay of local signaling molecules, and test our theory using quantitative models of receptor signaling. We will also study the emergent properties of the types of modular networks known to mediate downstream signaling in T cells and, building on these findings, test a new, simple theory of signal integration. This programme of work will produce a fuller understanding of decision-making by lymphocytes, and a richer framework for thinking about immunotherapy.