Clonal selection drives protective memory B cell responses in controlled human malaria infection
| Autor: | Gemma Pidelaserra Martí, G. Triller, Christian E. Busse, Hedda Wardemann, Thomas Höfer, Lisa Buchauer, Stephen L. Hoffman, Sumana Chakravarty, Elena A. Levashina, Rajagopal Murugan, Peter G. Kremsner, Katharina Imkeller, Giulia Costa, B. Kim Lee Sim, Benjamin Mordmüller, Cornelia Kreschel |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Plasmodium falciparum Immunology Naive B cell Protozoan Proteins Affinity maturation Mice 03 medical and health sciences 0302 clinical medicine Antigen Malaria Vaccines medicine Animals Humans Clonal Selection Antigen-Mediated Memory B cell B cell B-Lymphocytes biology Germinal center General Medicine Malaria Mice Inbred C57BL Circumsporozoite protein 030104 developmental biology medicine.anatomical_structure biology.protein Female Antibody 030215 immunology |
| Zdroj: | Science Immunology |
| ISSN: | 2470-9468 |
| Popis: | Affinity maturation, the clonal selection and expansion of antigen-activated B cells expressing somatically mutated antibody variants that develop during T cell-dependent germinal center reactions, is considered pivotal for efficient development of protective B cell memory responses to infection and vaccination. Repeated antigen exposure promotes affinity maturation but each time also recruits antigen-reactive naive B cells into the response. Here, we determined the relative impact of affinity maturation versus antigen-mediated clonal selection of naive B cells to mount potent B cell memory responses in humans after repeated exposure to a complex pathogen, the malaria parasite Plasmodium falciparum (Pf). Using single-cell immunoglobulin (Ig) gene sequencing and production of recombinant monoclonal antibodies, we analyzed the origin, development, and quality of memory B cell responses to Pf circumsporozoite protein (PfCSP), the major sporozoite surface protein. We show that after repeated immunization of Pf-naive volunteers with infectious Pf sporozoites (PfSPZ Challenge) under chloroquine prophylaxis (PfSPZ-CVac), the clonal selection of potent germline and memory B cell precursors against the central PfCSP NANP repeat outpaces affinity maturation because the majority of Ig gene mutations are affinity-neutral. Mathematical modeling explains how the efficiency of affinity maturation decreases strongly with antigen complexity. Thus, in the absence of long-term exposure, the frequency of antigen-reactive precursors and likelihood of their activation rather than affinity maturation will determine the quality of anti-PfCSP memory B cell responses. These findings have wide implications for the design of vaccination strategies to induce potent B cell memory responses against PfCSP and presumably other structurally complex antigens. |
| Databáze: | OpenAIRE |
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