eLife https://doi.org/10.7554/eLife.42475 & https://doi.org/10.7554/eLife.42498 (2019)

How T cell antigen receptors (TCRs) distinguish rare stimulatory ligands among a vast excess of non-stimulatory self peptides is a fundamental question of immunology. In eLife, Yousefi et al. and Tischer and Weiner investigate this question by complementary optogenetic approaches. The kinetic proofreading model is a useful framework with which to understand TCR ligand discrimination and states that the half-life of TCR–ligand interactions dictates signaling. However, investigating half-life without affecting other biophysical parameters has been technically very challenging. The studies in eLife use engineered receptors (either TCRs or chimeric antigen receptors) for which interactions with stimulatory ligand can be finely controlled in isolation by exposure to blue or red light. Through the use of either calcium flux or diacylglycerol accumulation as a ‘readout’ of T cell activation, these studies demonstrate that the kinetic proofreading model provides the most accurate description of TCR ligand discrimination.