a role for rebinding in rapid and reliable t cell responses to antigen重新绑定的角色快速和可靠的t细胞对抗原的反应.pdfVIP

A Role for Rebinding in Rapid and Reliable T Cell Responses to Antigen Omer Dushek1,2*, Raibatak Das1,3, Daniel Coombs1,2 1 Department of Mathematics, University of British Columbia, Vancouver, British Columbia, Canada, 2 Institute of Applied Mathematics, University of British Columbia, Vancouver, British Columbia, Canada, 3 Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada Abstract 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