| Abstract | In this talk I will first attempt to provide context for the symposium talks by providing a brief overview of membrane reactions, focusing on the regulation of the T cell antigen receptor (TCR) which is expressed on the surface of T cells. I will then discuss the role of TCR-antigen rebinding upon chemical dissociation in antigen discrimination by T cells. Antigen discrimination is the process by which T cells rapidly and specifically discriminate between potential stimuli based on the kinetic parameters of the T cell receptor – antigen bond. These antigenic molecules are presented among thousands of chemically similar endogenous peptides that may also bind TCR, raising the question of how T cells can accurately and rapidly make the decision to respond to certain antigens but not others. Using mathematical modeling and simulation tools we investigate the role of immediate T cell receptor – antigen rebinding in the rapid and reliable decision-making process. We show that including a signal persistence state in kinetic proofreading models allows individual receptors to integrate the duration of multiple binding events. Discrimination is achieved via an effective threshold in the sum of binding durations, a quantity that is sensitive not only to the off-rate but also to the on-rate. We conclude by discussing existing data that supports the notion that receptor/ligands undergo immediate rebinding at membrane interfaces and provide evidence that rebinding increases the potency of antigens. |
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