# Heterogeneity of plasma cell states is regulated by the dynamics of IRF4 expression

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2021 · $196,250

## Abstract

PROJECT SUMMARY
Protective antibody responses depend upon secreted immunoglobulin. This is regulated in a
stage-specific manner upon the differentiation of B cell blasts into plasma cells (PC) and depends
on the sequential upregulation of the IRF4 and Blimp-1 transcription factors. Together, they
orchestrate the plasma cell gene program that includes alternative processing of the
immunoglobulin transcript and the regulation of genes important for secretion of large quantities
of immunoglobulin, i.e. post-transcriptional and post-translational regulation, respectively. Despite
this understanding, a gap in knowledge exists in what elaborates the observed in vivo
heterogeneity of PC in regards to cell longevity, proliferative rates, tissue tropism, phenotypic
markers, and secretory rates. Specifically, it is not understood how this hierarchical regulatory
mechanism diversifies PC states, i.e. whether other regulators are engaged or whether the
dynamics of the network control distinct PC states. We have found that halving Irf4 gene copies
contributes to PC heterogeneity suggesting that the dynamics of the network diversifies PC states.
This proposal aims to elucidate the mechanisms whereby the dynamic of IRF4 expression
controls PC outcome. Furthermore, we will employ a newly developed reporter mouse that
enables simultaneous detection of cells expressing secretory and membrane Ig by two spectrally
distinct fluorescent proteins. Importantly, we expect this reporter system to function as a novel
and differentiation-stage-unbiased approach to study cells undergoing changes in IgH expression
levels and 3'end usage. Together, understanding the molecular basis of PC phenotypic and Ig
usage heterogeneity will enable future methodologies to test their relevance in diverse settings
which likely vary as a function of infection or pathologic states.

## Key facts

- **NIH application ID:** 10092104
- **Project number:** 5R21AI151610-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Roger Sciammas
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $196,250
- **Award type:** 5
- **Project period:** 2020-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10092104

## Citation

> US National Institutes of Health, RePORTER application 10092104, Heterogeneity of plasma cell states is regulated by the dynamics of IRF4 expression (5R21AI151610-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10092104. Licensed CC0.

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