Grant: Operating Grant

An effective immune response requires the cooperation of many different cell types, and clear communication between them is essential. I study a family of signalling molecules known as cytokines, soluble proteins that act as intercellular messengers, relaying instructions from one immune cell to another. This role gives cytokines a strategic importance in influencing the type and quality of the immune response. Misguided or persistent cytokine signals are hallmarks of damaging inflammatory diseases such as inflammatory bowel disease and asthma. Surprisingly little is known about how far or for how long cytokines signal. It has often been thought that the sender and recipient have to be in very close proximity, if not directly touching. In contrast, my data suggests that cytokine signals can spread widely, act indiscriminately, and affect very many cells. It is as if, instead of being whispered into the ear of a neighbour, cytokine instructions are delivered by megaphone and are heard by the whole crowd. The aim of this project is to find out how cytokines affect bystander cells, those not intended to be the primary target of the signal. Our hypothesis is that indiscriminate cytokine signalling changes the subsequent behaviour of bystander cells in multiple ways. We will test our hypothesis using a series of transgenic mice that allow us to analyse cytokine signalling and cytokine production as they happen, in a physiological immune system. Our goals are to determine the extent of indiscriminate cytokine signalling during an immune response, to test its impact on other immune responses, and to identify the mechanisms by which it operates. This is important because we believe that indiscriminate cytokine signalling contributes to the severity and spread of chronic inflammatory conditions, and an appreciation of the underlying mechanisms is an essential step in effective intervention.