Understanding T cell receptor (TCR) signalling requirements for thymic gamma/delta cell development; are gamma/delta cells selected through their TCR?. (360G-Wellcome-092973_Z_10_Z)

Gamma/delta T cells make robust non-redundant immune responses against a range of infections and cancers. However, surprisingly little is known about their basic biology. Indeed, although gamma/delta T cells recognise pathogens and tumours through their T cell receptors (TCRs), the individual identities of the TCR targets are still largely unknown. Moreover, how useful gamma/delta TCRs are selected during development in the thymus, and how gamma/delta T cells gain the specialised functional po tential that characterises their unique peripheral immune responses are equally unclear. This proposal seeks to provide important insight into how the characteristics of the gamma/delta TCR regulate the thymic development of gamma/delta T cells. We will test the idea that certain gamma/delta TCRs are positively or negatively selected, and have hypothesised that TCR signal strength at this stage of development fundamentally influences subsequent immune potential with specific reference to the pro duction of interferon-gamma and interleukin-17. Such knowledge will facilitate the search for both the microbial- and tumour-associated targets of the gamma/delta TCR, and should instruct the future refinement of immunotherapeutic strategies in the clinic.