# Regulation of B cell receptor avidity to organize antigen recognition

> **NIH NIH F31** · HARVARD MEDICAL SCHOOL · 2024 · $43,456

## Abstract

Project Summary / Abstract
This application proposes to define how B cell receptor binding site (BCRbs) copy number at the plasma
membrane surface is an actively regulated parameter that is developmentally tuned to optimize antigen
recognition and support affinity-driven antibody selection with B cell germinal centers. At the molecular scale,
increasing receptor binding site number can markedly increase affinity for ligand through the avidity effect,
formally defined as a reduction in binding off-rate. To define an analogous principle at the whole B cell level, I
have constructed a recombinant BCRbs counter, which for the first time measures the absolute number of
antigen binding sites on B lymphocytes. This counter consists of 1:1:1 stoichiometric complex of: one molecule
of a nanobody VHH (specific to the BCR light chain constant domain) + one fluorescent molecule linked through
one molecule of monomeric streptavidin. Using this tool, I will test the central hypothesis that BCR avidity is
developmentally regulated to promote antigen reception, and that this principle provides substrate for
B cell affinity selection following immune challenge. Aim 1 builds from my discovery that BCRbs number is
progressively increased during B lymphocyte development: first as IgM BCR on immature B cells emerging from
the bone marrow, through to transitional development in the periphery, and then to the mature IgM+/IgD+ antigen
receptive state that populates the lymphoid organs (e.g. lymph node and spleen). I will define how this
developmental enhancement of BCRbs avidity is achieved molecularly and whether it is conserved across both
mice and humans. Additionally, I will evaluate how BCRbs avidity can be differentially applied in mature B cells,
wherein I find that avidity is maximized in marginal zone B cells, which respond rapidly to bloodborne antigen in
the absence of affinity maturation. In Aim 2, I will evaluate BCRbs avidity as a parameter that organizes affinity-
driven selection within B cell germinal centers (GCs). Application of the BCRbs counter to GCs induced within a
mouse model of influenza virus infection reveals that antigen-specific B cells with higher BCRbs number are
selected for over time. Avidity (artificially increasing affinity through reduction of binding off rate) has the potential
‘buffer’ antibody binding strength by enabling selection of BCRs with weak monomeric affinity, and ultimately
contribute to the affinity ceiling long noted in antibody output. I will define this relationship by comparing copy
number of the BCR selected in the GC vs the actual in solution affinity value of its monomeric antigen binding
site. Collectively this proposal seeks to define BCR avidity as new parameter organizing B cell antigen
recognition.

## Key facts

- **NIH application ID:** 10993377
- **Project number:** 1F31AI186217-01
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Victoria Celine Rosado
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $43,456
- **Award type:** 1
- **Project period:** 2024-09-30 → 2027-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10993377

## Citation

> US National Institutes of Health, RePORTER application 10993377, Regulation of B cell receptor avidity to organize antigen recognition (1F31AI186217-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10993377. Licensed CC0.

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