A Stochastic Model of the Germinal Center Integrating Local Antigen Competition, Individualistic T-B Interactions, and B Cell Receptor Signaling
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...
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| Published in | The Journal of immunology (1950) Vol. 197; no. 4; pp. 1169 - 1182 |
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| Main Authors | , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
15.08.2016
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| 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. |
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| AbstractList | 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. 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. |
| Author | Lan, Yue-Heng Wang, Peng Shih, Chang-Ming Qi, Hai |
| Author_xml | – sequence: 1 givenname: Peng orcidid: 0000-0003-1988-657X surname: Wang fullname: Wang, Peng organization: Department of Physics, Tsinghua University, Beijing 100084, China; Collaborative Innovation Center of Quantum Matter, Beijing 100084, China – sequence: 2 givenname: Chang-Ming orcidid: 0000-0003-1111-0283 surname: Shih fullname: Shih, Chang-Ming organization: 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 – sequence: 3 givenname: Hai surname: Qi fullname: Qi, Hai email: lanyh@bupt.edu.cn, qihai@mail.tsinghua.edu.cn organization: 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 – sequence: 4 givenname: Yue-Heng surname: Lan fullname: Lan, Yue-Heng email: lanyh@bupt.edu.cn, qihai@mail.tsinghua.edu.cn organization: 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 |
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| SubjectTerms | B-Lymphocytes - immunology Germinal Center - immunology Humans Lymphocyte Activation - immunology Models, Immunological Models, Theoretical Receptors, Antigen, B-Cell - immunology Signal Transduction - immunology T-Lymphocytes - immunology |
| Title | A Stochastic Model of the Germinal Center Integrating Local Antigen Competition, Individualistic T-B Interactions, and B Cell Receptor Signaling |
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