Investigating the Effect of Antibody-Mediated Feedback on Ongoing Germinal Center Responses

<p>Antibodies play a crucial role in protection against a wide range of pathogens. As such, the goal of most vaccinations is to induce immune memory in the form of long-lasting, high-affinity serum antibody titers, which requires the participation of B cells in the germinal center (GC) response. It is well-established that pre-existing antibodies can influence the outcome of future humoral responses; however, whether antibody from an ongoing response can feedback onto contemporaneous GCs to influence B cell clonal selection and affinity maturation in real-time remains poorly understood. Here we present a genetic mouse tool to interrogate the effect of antibody-mediated feedback on ongoing GC responses. We have designed an oligoclonal B cell transfer mouse model with B cell receptor specificities to non-overlapping epitopes on the same antigen, allowing us to distinguish between epitope-specific and epitope-non-specific effects of secreted antibody. In addition, we have genetically engineered a Blimp-1-DTR mouse that allows for temporally controlled ablation of plasma cells and, therefore, depletion of antibody titers. Combining these two models has revealed that high levels of antibody produced during B cell responses can modulate interclonal selection in the GC by suppressing GC B cells that bind the same epitopes. However, a "traveling wave" of antibody is not required to guide intraclonal selection and, therefore, is not a driver of affinity maturation. We propose antibody-mediated suppression via epitope masking may be an important mechanism in guiding the development of primary GCs towards epitopes that are poorly represented in the serum antibody compartment, thereby maintaining diversity within humoral responses.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Thesis

Year

2024

Author dc:creator

• Barbulescu, Alexandru

Contributors dc:contributor

• Gabriel D. Victora

• antibody feedback
• germinal centers
• B cell affinity maturation
• epitope masking
• humoral immunity
• plasma cell ablation
• Life Sciences

Repository record dc:identifier

https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/750

OAI identifier oai:identifier

oai:digitalcommons.rockefeller.edu:student_theses_and_dissertations-1755