# Molecular control of germinal center selection and affinity maturation

> **NIH NIH R01** · ROCKEFELLER UNIVERSITY · 2024 · $542,400

## Abstract

PROJECT SUMMARY
Generation of high affinity antibodies in germinal centers (GCs) is a fundamental immunological process that
provides protection against infection. Antibody affinity maturation follows a prototypical Darwinian evolutionary
framework, in which rare GC B cells that acquire affinity-increasing mutations in the antigen-binding portions of
their immunoglobulin genes selectively undergo massive proliferation, leading to their expansion within the GC
population at the expense of lower-affinity clones. Through iterative rounds of selection and expansion, GC B
cells increase their affinity toward a particular pathogen or antigen, while being exported as memory or plasma
cells and contributing to the affinity of serum antibody over time.
GC B cells are among the fastest dividing mammalian cells and are uniquely equipped with a distinct cell cycle
program that allows them to divide every 4-6 hours. At its extreme, this robust expansion program can lead to
clonal bursts, in which a single B cell can take over a 2,000-cell GC in just a few days. Interestingly, GC B cells
can enter S phase in the apparent absence of mitogen, as if by “inertia,” hence their rapid mode of cell division
is termed “inertial cycling”. Notably, many of the key drivers of GC-derived B cell lymphoma, such as cyclin D3,
are critical for triggering and sustaining strong cell cycles in GC B cells. Despite its importance in the expansion
of high-affinity B cell clones and development of GC-derived lymphomas, the precise cellular dynamics and
molecular pathways that underlie inertial cycling of GC B cells remain poorly understood. This gap in our
understanding is primarily due to a lack of tools with the necessary spatial and temporal sensitivity to resolve GC
B cell cycles in vivo. The main goal of this research proposal is to define the cellular and molecular processes
that underly the unique cell cycle programs of GC B cells. To achieve this, we will characterize the spatiotemporal
dynamics of inertial cycling at a single cell level with intravital two-photon microscopy and fluorescent activity
sensors (Aim 1); and we will determine the principles that coordinate inertial cell cycling and mutability of B cell
receptors (Aim 2).
Completion of the proposed Aims will provide a comprehensive understanding of the specialized inertial mode
of GC B cell cycling and will contribute new insights into the fundamental mechanistic basis of how GCs select
for high affinity B cells. In addition, the findings from this proposed Aims will better our understanding of GC-
derived lymphomas, where inertial cycling becomes coopted for malignant transformation.

## Key facts

- **NIH application ID:** 11000020
- **Project number:** 2R01AI139117-06
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Gabriel D Victora
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $542,400
- **Award type:** 2
- **Project period:** 2018-08-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11000020

## Citation

> US National Institutes of Health, RePORTER application 11000020, Molecular control of germinal center selection and affinity maturation (2R01AI139117-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11000020. Licensed CC0.

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