# Cell decision underlying B-cell immune responses

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $426,959

## Abstract

Project Summary/Abstract
A hallmark of the humoral immune response is a two phased antibody response, the first being rapid and
providing for low affinity antibodies, and the second occurring with a week delay but providing high affinity
antibodies. An appropriate balance of both phases of the response is critical for an effective immune
response.
The two phased humoral immune response is governed by B-cell population dynamics that represent the
composite of the decisions made by individual cells whether to enter a growth phase and the cell cycle that
results in division, whether to survive or die, and whether to differentiate into antibody secreting plasma cells
and/or memory B-cells. At any given timepoint there is a great variety of B-cell fates, and prior studies
assumed that this is due to stochastic fate decisions by individual cells at each generation. Instead, our
recently established long-term microscopy workflow revealed that cells make highly deterministic fate
decisions, and that the cell-to-cell variability within the population is largely due to heterogeneity in the founder
cells. This renders humoral immunity substantially more predictable, so long as we have a mechanistic
understanding of how molecular networks control B-cell decision making in proliferation and differentiation.
The overarching goal of the proposed project is to develop quantitative understanding and multi-scale model of
how the multi-dimeric NFκB system controls B-cell decision making to effect cell survival, proliferation, and
differentiation.
The overarching hypothesis of the proposed studies is that the coordinated dynamics of NFκB family members
RelA and cRel control the phasing of B-cell proliferation and differentiation and thus the affinity, abundance
and diversity of antibodies and hence efficacy of the humoral immune response.
We will address this hypothesis with an iterative systems biology approach structured into following three
Specific Aims:
 1. Delineate how NFκB system dynamics control the lineages of proliferating B-cells
 2. Delineate how NFκB system dynamics control plasma B-cell differentiation
 3. NFκB system control of humoral immunity in vivo: phasing low and high affinity antibody responses
Each Aim involves novel multiscale mathematical modeling and quantitative experimentation, including
unprecedented long term microscopy, novel fluorescent reporter mouse strains, and single cell genomic
technologies.

## Key facts

- **NIH application ID:** 10094180
- **Project number:** 5R01AI132731-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Alexander Hoffmann
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $426,959
- **Award type:** 5
- **Project period:** 2018-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10094180

## Citation

> US National Institutes of Health, RePORTER application 10094180, Cell decision underlying B-cell immune responses (5R01AI132731-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10094180. Licensed CC0.

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