# Tissue-engineered Aged B Cell Immune Organoid to Study Antibody Secreting Cell Differentiation Trajectory

> **NIH NIH R56** · GEORGIA INSTITUTE OF TECHNOLOGY · 2023 · $324,310

## Abstract

RESEARCH SUMMARY
Aged individuals, who are often at higher risk of fatality in life-threatening infectious diseases, do not form high-
quality antibodies against new infections. Humoral immunity against infections depends on the germinal center
(GC) differentiation process in the B cell follicles of lymph nodes. In GCs, naïve B cells rapidly proliferate in
response to T cell-dependent antigens and somatically mutate into high-affinity antibody-secreting cells, i.e.,
plasma cells. B cells assume heterogeneous cell fates upon stimulation in young mice, with only a fraction
differentiating into antibody-secreting cells (ASC). Notably, plasma cell differentiation is controlled by multiple
cell division-coupled epigenetic programs. Chromatin accessibility changes correlate with gene expression and
reveal the reprogramming of transcriptional networks and the genes they regulate at specific cell divisions. A
subset of genes in naive B cells display accessible promoters in the absence of transcription and are marked by
the histone modification H3 lysine 27 trimethylation (H3K27me3), a Polycomb protein Enhancer of zeste homolog
2 (EZH2) catalyzed repressive modification. Such genes encode regulators of cell division and metabolism and
include the essential plasma cell transcription factor Blimp-1. Consequently, chemical inhibition of EZH2 results
in enhanced plasma cell formation. A significant concern is that with aging, B cells exhibit a decreased expansion
of B cells and GC reaction in response to antigen partly due to immune senescence and a defective follicular T
helper cell (TFH) system. As a result, aged mice cannot generate sufficient GCs to provide insight into ASC fate
and epigenomic remodeling of GC B cells, necessitating the development of a tissue-engineered model of an
aged lymph node. Therefore, the long term goal of this R01 is to develop an ex vivo “aged B cell follicle” organoid
technology capable of inducing early GC programming of aged B cells from both mice and humans and enabling
the study of plasma cell fate and regulation of the epigenome of B cells to identify checkpoint targets that can be
suppressed to boost GC response in aged B cells. The R01 brings together a multidisciplinary team of experts
in GC organoids, vaccine, adjuvants, and lymphoid tissue engineering (Ankur Singh, PI, Georgia Tech) and GC
immunology, ASC fate mapping and epigenomics (Jeremy Boss, Co-I, Emory Medicine), and microenvironment
spatial omics (Ahmet Coskun, Co-I, Georgia Tech).

## Key facts

- **NIH application ID:** 10804886
- **Project number:** 1R56AG075080-01A1
- **Recipient organization:** GEORGIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Ankur Singh
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $324,310
- **Award type:** 1
- **Project period:** 2023-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10804886

## Citation

> US National Institutes of Health, RePORTER application 10804886, Tissue-engineered Aged B Cell Immune Organoid to Study Antibody Secreting Cell Differentiation Trajectory (1R56AG075080-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10804886. Licensed CC0.

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