T cells use their T-cell receptors (TCRs) to discriminate between lower-affinity self and higher affinity non-self pMHC antigens. Although this process has been widely studied, the underlying mechanisms remain unclear. In particular, it is presently unclear whether co-signalling receptors, including those routinely used for cancer immunotherapy (e.g. PD-1), only impact antigen sensitivity or also impact antigen discrimination. The objective of this project will be to investigate the contribution of various co-signalling receptors to the process of antigen discrimination by T cells and to exploit this information to improve T cell therapies as appropriate. The work will rely on primary human T cells transduced or transfected with a defined TCR to which a panel of pMHC antigens have been identified that bind with a spectrum of affinities (as described in Pettmann et al (2021) eLife). By tampering with individual co-signalling receptors, their impact on antigen sensitivity and discrimination can be quantitatively assessed and rationally exploited for improved T cell based therapies.