title: A Stochastic Model of the Germinal Center Integrating Local Antigen Competition, Individualistic T-B Interactions, and B Cell Receptor Signaling.
abstract: The germinal center (GC) reaction underlies productive humoral immunity by orchestrating competition-based affinity maturation to produce plasma cells and memory B cells. T cells are limiting in this process. How B cells integrate signals from T cells and BCRs to make fate decisions while subjected to a cyclic selection process is not clear. In this article, we present a spatiotemporally resolved stochastic model that describes cell behaviors as rate-limited stochastic reactions. We hypothesize a signal integrator protein integrates follicular helper T (Tfh)- and Ag-derived signals to drive different B cell fates in a probabilistic manner and a dedicated module of Tfh interaction promoting factors control the efficiency of contact-dependent Tfh help delivery to B cells. Without assuming deterministic affinity-based decisions or temporal event sequence, this model recapitulates GC characteristics, highlights the importance of efficient T cell help delivery during individual contacts with B cells and intercellular positive feedback for affinity maturation, reveals the possibility that antagonism between BCR signaling and T cell help accelerates affinity maturation, and suggests that the dichotomy between affinity and magnitude of GC reaction can be avoided by tuning the efficiency of contact-dependent help delivery during reiterative T-B interactions.
authors.affiliation: Department of Physics, Tsinghua University, Beijing 100084, China; Collaborative Innovation Center of Quantum Matter, Beijing 100084, China;
authors.forename: Peng
authors.identifier: 0000-0003-1988-657X
authors.initials: P
authors.lastname: Wang
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China; Institute for Immunology, Tsinghua University, Beijing 100084, China; and Department of Basic Biomedical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Chang-Ming
authors.identifier: 0000-0003-1111-0283
authors.initials: CM
authors.lastname: Shih
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China; Institute for Immunology, Tsinghua University, Beijing 100084, China; and Department of Basic Biomedical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China lanyh@bupt.edu.cn qihai@mail.tsinghua.edu.cn.
authors.forename: Hai
authors.initials: H
authors.lastname: Qi
authors.affiliation: Department of Physics, Tsinghua University, Beijing 100084, China; Collaborative Innovation Center of Quantum Matter, Beijing 100084, China; lanyh@bupt.edu.cn qihai@mail.tsinghua.edu.cn.
authors.forename: Yue-Heng
authors.initials: YH
authors.lastname: Lan
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology*; D018858:Germinal Center / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D018448:Models, Immunological; D008962:Models, Theoretical; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D011947:Receptors, Antigen, B-Cell