2010/03/06 by Philippos K. Tsourkas, Tsourkas, Philippos K., Subhadip Raychaudhuri +1
Immunology and Microbiology · #Biological Physics (physics.bio-ph) #Cell Behavior (q-bio.CB) #FOS: Biological sciences #FOS: Physical sciences #Immune Cell Function and Interaction #Immunotherapy and Immune Responses #T-cell and B-cell Immunology
paper · pdf · doi:10.48550/arxiv.1003.1415
openalex publication_date 2010/03/06 · openalex created_date 2022/09/29 · openalex updated_date 2026/07/28
B cells signaling in response to antigen is proportional to antigen affinity,\na process known as affinity discrimination. Recent research suggests that B\ncells can acquire antigen in membrane-bound form on the surface of\nantigen-presenting cells (APCs), with signaling being initiated within a few\nseconds of B cell/APC contact. During the earliest stages of B cell/APC\ncontact, B cell receptors (BCRs) on protrusions of the B cell surface bind to\nantigen on the APC surface and form micro-clusters of 10-100 BCR/Antigen\ncomplexes. In this study, we use computational modeling to show that B cell\naffinity discrimination at the level of BCR-antigen micro-clusters requires a\nthreshold antigen binding time, in a manner similar to kinetic proofreading. We\nfind that if BCR molecules become signaling-capable immediately upon binding\nantigen, there is a loss in serial engagement due to the increase in bond\nlifetime as koff decreases. This results in decreasing signaling strength as\naffinity increases. A threshold time for antigen to stay bound to BCR before\nthe latter becomes signaling-capable favors high affinity BCR-antigen bonds, as\nthese long-lived bonds can better fulfill the threshold time requirement than\nlow-affinity bonds. A threshold antigen binding time of ~10 seconds results in\nmonotonically increasing signaling with affinity, replicating the affinity\ndiscrimination pattern observed in B cell activation experiments. This time\nmatches well (within order of magnitude) with the experimentally observed time\n(~ 20 seconds) required for the BCR signaling domains to undergo antigen and\nlipid raft-mediated conformational changes that lead to association with Syk.\n