# Determinants of follicular helper T cell expansion in lupus

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2020 · $632,061

## Abstract

Project Summary/Abstract
The expansion of follicular helper (Tfh) cells and related subpopulations is correlated with the severity of human
lupus disease and is shared by all lupus-prone mouse models. However, the mechanisms for the expansion of
Tfh cells in lupus are largely unknown. Thus, the objective of this proposal is to shed new light on the mechanisms
that are responsible for Tfh cell expansion in lupus using innovative cellular and molecular approaches based
on the obtained data from the B6.Sle1.Sle2.Sle3 triple congenic (TC) murine model of lupus. Accordingly, we
have identified genetic, as well as microbial and metabolic determinants that modulate lupus Tfh cell expansion.
Transferring the perturbed gut microbiota of lupus mice into mouse host crucially contributed to Tfh cell
expansion. Additionally, an altered tryptophan (Trp) metabolism also enhanced Tfh cell expansion, which was
reduced by manipulating dietary Trp levels in mice. Finally, inhibiting glycolysis with 2-deoxi-D-glucose (2DG),
or glutaminolysis with 6-Diazo-5-oxo-L-norleucine (DON) functionally diminished lupus Tfh cell differentiation.
Our hypothesis is that the expansion of Tfh cells implicated in lupus integrates cues from susceptibility genes,
dysregulated microbiome and environmental metabolites. In support of this hypothesis, our data demonstrate
that TC Tfh cells possess a novel metabolic gene signature, potentially driving the autoreactive Tfh cell expansion
directed by a unique metabolic flux. Thus, we propose combining the analyses of Tfh cell transcriptome and
metabolome in response to variations of the aforementioned cues as a means to elucidate the involved molecular
mechanisms, singly or in combination, impacting the fate of Tfh cells in lupus. We also propose to investigate
the effects of genetic and environmental determinants functionally affecting Tfh cells on two B cell subsets,
CD11c+Tbet+ B cells (ABCs) and IgA+ B cells. To proceed, the following Specific Aims are proposed. 1. To
explore the mechanisms by which lupus susceptibility genes modulate the Tfh cell transcriptome and
metabolome in the two unrelated TC and (NZW x BXSB.Yaa)F1 lupus models. 2. To identify the impact of
environmental factors on the Tfh transcriptome and metabolome in TC mice. And 3. To elucidate the molecular
mechanisms implicated in the expansion of Tfh cells in lupus patients. Obtained results from these mechanistic
experiments will be the first in-depth investigation of Tfh cell expansion directed by environmental and genetic
determinants, which may be reprogrammed for a sustainable therapeutic strategy to perhaps improve lupus
patients' health.

## Key facts

- **NIH application ID:** 10065726
- **Project number:** 1R01AI154630-01
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Laurence Morel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $632,061
- **Award type:** 1
- **Project period:** 2020-07-08 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10065726

## Citation

> US National Institutes of Health, RePORTER application 10065726, Determinants of follicular helper T cell expansion in lupus (1R01AI154630-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10065726. Licensed CC0.

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