Weaponizing T-cell receptors through molecular engineering.

T-cell receptors (TCRs) recognize pathogens to ignite immune responses, making them attractive scaffolds for development as immunotherapeutics. However, manipulation of TCRs has been impeded by difficulties in their engineering and expression. Wagner and colleagues now establish new platforms to generate high-affinity TCR variants that potently activate T cells, and they also create soluble TCR fusion proteins that specifically recognize cognate peptides. This work provides specific tools to combat cytomegalovirus (CMV) infection and helps illuminate a general path to actuation of engineered TCR-based therapeutics.