A role for rebinding in rapid and reliable T cell responses to antigen

• Published in: PLoS computational biology 2009-11, Vol.5 (11), p.e1000578-e1000578
• Main Authors: Dushek, Omer, Das, Raibatak, Coombs, Daniel
• Format: Article
• Language: English
• Subjects: Animals; Antigens; Antigens - immunology; Biophysics/Cell Signaling and Trafficking Structures; Biophysics/Theory and Simulation; Cell Biology/Cell Signaling; Computer Simulation; Editing; Experiments; Humans; Immune system; Immunity, Innate - immunology; Immunology; Immunology/Antigen Processing and Recognition; Lymphocytes; Mathematical models; Models, Neurological; Peptides; Receptors, Antigen, T-Cell - immunology; T cell receptors; T cells; T-Lymphocytes - immunology
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1000578

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.