# Defining the role of T cell help in germinal centers by intercellular enzymatic labeling

> **NIH NIH R01** · ROCKEFELLER UNIVERSITY · 2022 · $785,027

## Abstract

PROJECT SUMMARY
Generation of high affinity antibodies in germinal centers (GCs) is a critical step in a wide variety of clinically
relevant processes, from protection against pathogens by prior infection or vaccination to the development of
allergies and autoimmune diseases. Antibody affinity maturation follows a prototypical Darwinian framework, in
which GC B cells introduce random mutations into the antigen-binding portions of their immunoglobulin (Ig)
genes, generating variations in affinity within their progeny. Rare B cells that acquire affinity-increasing mutation
are then selectively expanded within the GC population, thus increasing the average affinity of GC B cells as a
whole, in a process we refer to as positive selection.
Despite decades of work, the precise cellular mechanisms of positive selection—in other words, how GCs “pick
out” B cells with the highest affinity—remains a topic of debate. More than 10 years ago, we provided the first in
vivo evidence in mice for a role for T follicular helper (Tfh) cells as arbiters of this selective process. In our model,
Tfh cells would sense how much peptide a B cell could present on its surface (which in turn depended on the B
cell’s affinity), providing help selectively to the highest-affinity B cells. However, despite accumulating functional
evidence for this model, selective delivery of T cell help to B cells based on their affinity has never been directly
demonstrated in physiological settings. To achieve this, we developed LIPSTIC, a method that allows us to
directly record T cell help to B cells with great precision in vivo. In Aim 1 of this project, we propose to use
LIPSTIC as a means to directly test the T cell help model in classic hapten-carrier induced GC selection models.
In Aim 2, we will follow up on this by testing our findings from mouse LIPSTIC in human vaccine-induced GCs.
In Aim 3, we use the original LIPSTIC in conjunction with two novel versions on this strategy to investigate the
dynamics of multi-antigen driven selection in influenza-induced GCs.

## Key facts

- **NIH application ID:** 10566601
- **Project number:** 1R01AI173086-01
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Gabriel D Victora
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $785,027
- **Award type:** 1
- **Project period:** 2022-09-21 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10566601

## Citation

> US National Institutes of Health, RePORTER application 10566601, Defining the role of T cell help in germinal centers by intercellular enzymatic labeling (1R01AI173086-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10566601. Licensed CC0.

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