# Targeting follicular helper CD4 T cells in SLE

> **NIH NIH R37** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2024 · $461,247

## Abstract

Project Summary/Abstract
High affinity class-switched autoantibodies (autoAb) are the major pathogenic effector molecules in lupus. They
are generated by B cells that differentiate through either the germinal center (GC) or the extrafollicular (EF)
pathways. The frequency of follicular helper (Tfh) cells and EF helper (eTf) CD4+ T cells are expanded in lupus
in direct correlation with disease activity. The EF pathway has been best characterized in the MRL/lpr lupus-
prone mice with AM14 BCR Tg B cells, which have been used as a model of autoreactive B cells activated
through dual BCR and TLR9 signals. Overall, the GC and EF pathways are crucial nodes of lupus pathogenesis
and lupus-prone mice present validated models for mechanistic studies of these pathways. We and others have
shown that the metabolism of immune cells was altered in lupus patients and mice, and that some of these
alterations offer therapeutic targets. Relatively little is known on the metabolic programs that sustain either
autoreactive or immunization-induced (Imm-) GC B cells and Tfh cells, and nothing is known about the
metabolism of EF activation. We have shown during the first cycle of funding that the production of anti-dsDNA
IgG but not Imm-Abs, was glucose-dependent. In contrast, both autoAbs and Imm-Abs were eliminated by the
inhibition of glutaminolysis. These results obtained with bulk polyclonal populations treated with metabolic
inhibitors his led us to hypothesize that autoAbs and Imm-Abs have different metabolic requirements through
the GC stage, which could be ultimately translated in their selective targeting. In this competitive renewal, we
propose to use auto- and Imm-Ig-specific B and T cells, as well as GC B and Tact-specific deletions of metabolic
enzymes to determine the intrinsic metabolic requirements of autoreactive and Imm-GC B and Tfh cells at the
antigen- and cell-specific levels. We also propose to address the metabolic requirements of EF activation of
autoreactive B cells. Using unique mouse models and a combination of scRNA-Seq and deep metabolomic
analyses, we propose three specific aims to determine the requirements in glucose (1), glutamine (2), and
FAO (3) for autoAb vs. Imm-Ab production, and to identify the corresponding mechanisms. These
experiments will help to define the specific metabolic requirements of the B and CD4+ T cells that participate in
the production of lupus autoAbs. This knowledge may ultimately identify means to eliminate autoAb production
while preserving protective humoral autoimmunity.

## Key facts

- **NIH application ID:** 10876955
- **Project number:** 5R37AI128901-08
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Laurence Morel
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $461,247
- **Award type:** 5
- **Project period:** 2016-12-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10876955

## Citation

> US National Institutes of Health, RePORTER application 10876955, Targeting follicular helper CD4 T cells in SLE (5R37AI128901-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10876955. Licensed CC0.

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