Understanding the CD28-CTLA-4 pathway: a thermostat for T cell immunity

The CD28-CTLA-4 pathway controls T cell immune responses to both foreign and self-antigens, where loss of CD28 compromises adaptive immunity and loss of CTLA-4 causes fatal autoimmunity. The system is regulated by two distinct ligands CD80 and CD86, which bind with different affinity, avidity and valency characteristics to CD28 and CTLA-4. The binding of another ligand (PD-L1) to CD80, alters these characteristics and directly connects CD28, CTLA-4 and CD80 to the PD-1 pathway. Despite this critical position in controlling immunity, the fundamental mechanisms underpinning these pathways remain poorly understood. In this proposal we hypothesise that the integrated CD28-CTLA-4-PD-1 pathway represents a tunable "thermostat" that is regulated by a series of ligand-receptor interactions, competitions and feedbacks that control T cell outcomes. We propose to: a) Understand how biophysical characteristics of ligand-receptor interactions control pathway behaviour, by acting in concert. b) Determine how natural and engineered changes in these biophysical characteristics alter T cell responses in vitro and in vivo. c) Generate mathematical models to predict outcomes and look for emergent behaviours. We therefore aim to provide a fully integrated view of how this essential immune regulatory system works, from molecular detail through to immune function.