# Oligoclonal T Cell Expansion and Rheumatoid Arthritis

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2020 · $215,808

## Abstract

Project Summary
The breakdown of T cell tolerance is a pinnacle pathogenic event in rheumatoid arthritis (RA) and precedes
the onset of clinical disease by decades. Molecular analyses of T cells supported by this project has led to the
discovery that RA T cells are prematurely aged and that senescence supports proinflammatory effector functions.
Recent work has connected maldifferentiation of RA T cells with abnormalities in their energy supply and
metabolism. Metabolic abnormalities are present in naïve CD4 T cells, long before they participate in synovial
inflammation, opening the intriguing possibility to prevent autoimmunity by metabolic interference. Naïve CD4 T
cells in RA patients downregulate the glycolytic enzyme Phosphofructokinase 2 (PFKFB3) and upregulate
Glucose-6-phosphate dehydrogenase (G6PD); therefore shunting glucose into the pentose phosphate
pathway (PPP). This metabolic abnormality leads to an oversupply of reductive elements (NADPH) and
consumption of reactive oxygen species (ROS), resulting in defective oxidant signaling. Mostly affected is the
redox-sensing protein kinase Ataxia telangiectasia mutated (ATM), which controls cell cycle behavior. With ATM
insufficiency, RA T cells hyperproliferate, loose quiescence and make an early commitment to IL-17 and IFN-
γ production. This project will define molecular mechanisms that connect metabolic and functional abnormalities
in RA T cells, with the aim to identify actionable diagnostic and therapeutic targets. We have developed a panel
of pharmacologic and genetic manipulations to mimic PPP overutilization in human T cells, enabling a
mechanistic exploration of T cell metabolism and function. Specific Aim 1 will seek to understand how glucose
shunting into the PPP, accumulation of NADPH and loss of ROS affects T cell differentiation, survival and
senescence; with a special emphasis on the induction of disease-relevant T follicular helper cells and Treg cells.
Specific Aim 2 will determine how metabolic reprogramming affects the interaction of T cells with B cells,
osteoclast precursors and synoviocytes to clarify its impact on autoantibody production, bone erosion and
synovial hyperplasia. In Specific Aim 3, we will examine the regulatory role of inflammatory signals in the
glycolytic machinery, specifically in the induction and suppression of PFKFB3 and G6PD. Specific Aim 4 is
designed to discover how oxidant signaling shapes T cell differentiation and lineage commitment. By focusing
on ATM, AMPK and mTOR we will define relevant signaling pathways and identify small molecule reagents that
can restore ATM and AMPK activation, thus restraining mTOR and mTOR-dependent inflammation.

## Key facts

- **NIH application ID:** 10457108
- **Project number:** 7R01AR042527-24
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Cornelia M. Weyand
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $215,808
- **Award type:** 7
- **Project period:** 1993-09-30 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10457108

## Citation

> US National Institutes of Health, RePORTER application 10457108, Oligoclonal T Cell Expansion and Rheumatoid Arthritis (7R01AR042527-24). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10457108. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*