A Role for Rebinding in Rapid and Reliable T Cell Responses to Antigen

Experimental work has shown that T cells of the immune system rapidly and specifically respond to antigenic molecules presented on the surface of antigen-presenting-cells and are able to 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, raising the question of how T cells can reliably make a decision to respond to certain antigens but not others within minutes of encountering an antigen presenting cell. In this theoretical study, we investigate the role of localized rebinding between a T cell receptor and an antigen. We show that by allowing the signaling state of individual receptors to persist during brief unbinding events, T cells are able to discriminate antigens based on both their unbinding and rebinding rates. We demonstrate that T cell receptor coreceptors, but not receptor clustering, are important in promoting localized rebinding, and show that requiring rebinding for productive signaling reduces signals from a high concentration of endogenous pMHC. In developing our main results, we use a relatively simple model based on kinetic proofreading. However, we additionally show that all our results are recapitulated when we use a detailed T cell receptor signaling model. We discuss our results in the context of existing models and recent experimental work and propose new experiments to test our findings.Author Summary: T cells are essential players in the immune response to pathogens such as viruses and bacteria. They can be activated to respond when they recognize molecular signatures of infection (antigens) on the surface of antigen-presenting-cells of the immune system. The T cell response is highly specific (a particular T cell responds to only the right antigen), sensitive (a T cell will respond to as few as 1–10 antigens) and speedy (antigen binding may induce signaling within seconds). We wish to understand how the T cell, using its surface antigen receptors, is able perform this task. To do this, we developed mathematical models of antigens binding and unbinding from T cell surface receptors. Our primary finding is that T cells can discriminate antigens based on both their binding and unbinding rates from the T cell antigen receptor. We examine potential impacts of T cell antigen receptor clustering, T cell surface coreceptor molecules, and background self-antigens on this process.