# Dissecting the role of geranylgeranyl glutathione in the germinal center response

> **NIH NIH F30** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $45,164

## Abstract

PROJECT SUMMARY / ABSTRACT
As the key site for orchestrating the production of high affinity antibody, the germinal center (GC) plays an
important role in mounting effective humoral immune responses. The GC is characterized by a complex,
chemokine-driven organization of cells, and GC B cells are tightly confined to this anatomic space, lacking the
ability to recirculate. This confinement fosters interactions of the GC B cells with supporting T follicular helper
cells (Tfh) and antigen loaded follicular dendritic cells (FDCs), and ensures B cell selection and somatic
hypermutation events occur in a well-controlled microenvironment. Furthermore, confinement is hypothesized
to contribute to the development of GCs as separate `cellular islands,' allowing the evolution of distinct high
affinity clones. Thus, GC confinement is thought to allow for the generation of an antibody response that is not
only high in affinity but also diverse in specificity. Past work in our lab provided evidence that two Ga13-
coupled GPCRs, P2RY8 and S1PR2, promote the confinement and clustering of human GC B cells within the
GC by inhibiting their outward migration. These receptors and their downstream effector Ga13 can be mutated
in up to 60% of some GC B cell-derived lymphomas, underscoring their essential role in human health. The lab
recently identified the endogenous ligand for P2RY8 as geranylgeranyl-glutathione (Ggg), showing Ggg inhibits
migration of human GC B cells and Tfh cells with nM potency. However, the enzymes and transporters
involved in the in vivo production, export and degradation of this novel intercellular signaling molecule have not
yet been defined. Our lab has found the γ-glutamyltransferase-5 (Ggt5) enzyme capable of degrading Ggg and
confirmed the expression of this enzyme by FDCs within primary follicles and GCs. Preliminary data also
supports that the transporter Abcc1 may be controlling release of Ggg from cells. The goal of my PhD studies
and this proposal is to elucidate the role of the newly discovered metabolite Ggg in the GC response.
Based on preliminary data, I hypothesize that the precisely controlled distribution of Ggg within the
follicle is necessary for the confinement of GC cells and thus for the mounting of an effective B cell
response. In Aim 1, I will define the enzymes and transporters involved in Ggg metabolism and examine their
distribution in vivo to understand how the Ggg gradient is established. In Aim 2, I will determine the role of the
Ggg gradient in promoting GC confinement via disruption of the gradient in Ggt5 KO mice. In Aim 3, I will
characterize the function of the P2RY8-Ggg axis in human GCs using tonsil slice organ culture. This work will
provide new mechanistic understanding for how the Ggg gradient is generated in vivo and may lead to the
development of therapeutics designed to modulate it. Given the frequent mutation of P2RY8 in a spectrum of
cancers and the ability of a wide range of cell types to produce G...

## Key facts

- **NIH application ID:** 10304180
- **Project number:** 5F30AI150061-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Antonia Gallman
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $45,164
- **Award type:** 5
- **Project period:** 2019-12-14 → 2022-09-13

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10304180

## Citation

> US National Institutes of Health, RePORTER application 10304180, Dissecting the role of geranylgeranyl glutathione in the germinal center response (5F30AI150061-03). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10304180. Licensed CC0.

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