# Defining how TCR strength of signal modulates Treg function

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $607,401

## Abstract

Abstract/Summary
Millions of people worldwide have been diagnosed with autoimmune diseases such as multiple sclerosis (MS).
The hallmark of MS is progressive demyelination driven by an inappropriate immune response that attacks
cells within the central nervous system. The dominant risk factor for MS, and experimental autoimmune
encephalomyelitis (EAE) animal models, in addition to many other autoimmune diseases (type I diabetes,
rheumatoid arthritis, etc) is specific MHC class II molecules. Since MHC class II presents peptide antigen to
both CD4+ T conventional (Tconv) and regulatory T cells (Tregs), the interaction between the T cell receptor
(TCR) and self peptide:MHC (pMHC) plays a pivotal role in autoimmune disease progression. The vital
purpose of Tregs is to suppress immune responses against self in an antigen specific manner. Tregs recognize
antigen such as myelin via their TCR, yet the fundamental measures and the underlying mechanism of TCR
interaction with pMHC is unknown. Therefore, a thorough understanding of the antigen-specific reactivity of
Tregs and whether this activity could be exploited has significant therapeutic potential. Here, we will dissect the
interaction between TCR and myelin antigen using sensitive technologies to measure biophysical properties of
TCR binding such as affinity and bond lifetimes. Of note, Tregs apply force to the bond between TCR and
pMHC, which is ultimately reflected by changes in how long the proteins interact. While Treg TCRs are said to
have enhanced strength of signal, mechanistically this concept is poorly defined. We discovered that
suppressive Tregs apply more force to the pMHC bond than do Tconv cells. In addition, myelin-specific Tregs
that fail to suppress apply lower levels of force. We therefore hypothesize that during antigen recognition, the
increased magnitude of force determines the Treg suppressive phenotype. We have designed three aims to
test this hypothesis that will: 1) compare antigenic binding parameters of functional versus defective Tregs; 2)
determine Treg functional parameters dependent on the magnitude of force; and 3) engineer TCR sequences
to decouple affinity, bond lifetime, and the level of force in response to self antigen. Thus, our project will
provide novel insight into the mechanisms governing Treg function and dysfunction during demyelinating
autoimmune disease. Our work will be the first to investigate various levels of force as a potent biomarker for
Treg that dictates their suppressive efficacy, potency, and phenotypic stability.

## Key facts

- **NIH application ID:** 10891503
- **Project number:** 5R01AI169835-03
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Brian D Evavold
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $607,401
- **Award type:** 5
- **Project period:** 2022-09-19 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891503

## Citation

> US National Institutes of Health, RePORTER application 10891503, Defining how TCR strength of signal modulates Treg function (5R01AI169835-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10891503. Licensed CC0.

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