# Targeting follicular helper CD4 T cells in SLE

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2020 · $381,250

## Abstract

Project Summary/Abstract
This proposal intends to characterize Tfh cells, a population that is critical for disease development and
maintenance in SLE and test the novel hypothesis that SLE-Tfh are uniquely sensitive to metabolic inhibition, a
feature that can be exploited to therapeutic intervention. The scientific premise of this proposal is based on
three lines of evidence: 1. The necessary role of Tfh cells for the production of pathogenic autoAbs in lupus
has been well-established in SLE patients and mouse models; 2. Tfh cells induced by immunization are
metabolically quiescent, a fact that we have confirmed showing that they are not affected by glucose inhibitors
in lupus-prone and control mice; and 3. We have strong preliminary data showing that SLE-Tfh cells from four
different mouse models of lupus are sensitive to glucose.
We propose the hypothesis that spontaneous Tfh cells supporting the production of autoAbs (SLE-Tfh) have a
different metabolism than Tfh cells providing protective humoral immunity against pathogens (TD-Tfh) in either
lupus or normal mice. Based on similarities of CD4+ T cell functions and metabolism in lupus-prone mice and
SLE patients, we also hypothesize that the expanded Tfh cells in SLE patients also have a different
metabolism than that of health controls (HCs). Consequently, we predict that targeting Tfh cellular metabolism
provides an effective approach to treat lupus without compromising the patients’ protection against TD-
pathogens. We propose to test these hypotheses using cellular and molecular immunology approaches in
mouse models as well as with human PBLs with the three following specific aims
1. To define the molecular and metabolic signatures of SLE-Tfh as compared to TD-Tfh cells
elicited by TD-dependent Ags (PR8 flu virus and NP-OVA) in lupus mice and B6 controls. The
immunophenotypes, anatomical location, gene expression, and metabolic profile of spontaneous Tfh cells in
TC and B6.lpr mice will be compared to that of flu-specific I-A(b) NP-tetramer positive Tfh cells in TC, B6.lpr
and B6 mice infected with PR8 virus. In addition to these polyclonal T cell models, we will use an adoptive
transfer model of OVA-specific OT-II T cells carrying the Sle1 lupus susceptibility allele that favors the
expansion of Tfh cells (9) into NP-OVA immunized mice (10). This aim will define the functional differences
between TD-Tfh and SLE-Tfh cells in two models of lupus and with two different TD-immunizations.
2. To define the response of SLE-Tfh and TD-Tfh cells to glucose inhibition in the mouse. Using the
same experimental systems as in SA1, we will compare the responses of SLE-Tfh cells and TD-Tfh cells to
glucose inhibition in mice treated with 2DG, a glucose analog that blocks the first reaction of glycolysis.
3. To compare the molecular and metabolic signatures of circulating cTfh cells in SLE patients and
HCs, as well as their response to metformin. We hypothesize that the expansion of cTfh cells in SLE
pat...

## Key facts

- **NIH application ID:** 9828613
- **Project number:** 5R01AI128901-04
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Laurence Morel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2016-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828613

## Citation

> US National Institutes of Health, RePORTER application 9828613, Targeting follicular helper CD4 T cells in SLE (5R01AI128901-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9828613. Licensed CC0.

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