# Inducing Tolerance with 5-Module chimeric Antigen Receptor (5MCAR) T Cells

> **NIH NIH R56** · UNIVERSITY OF ARIZONA · 2020 · $777,783

## Abstract

PROJECT SUMMARY
T cells respond to peptide antigens presented by MHC molecules (pMHC). They are driven by 5-module
macrocomplexes, composed of one receptor module [the T cell receptor (TCR)], three signaling modules
(CD3δε, CD3γε, CD3ζζ), and a CD4 or CD8 coreceptor module, that allow T cells to respond to a single
agonist pMHC and direct differentiation to cytotoxic (CTL), helper (Th), regulatory (Treg), or memory (Tm) cell
phenotypes that are essential for productive immunity. Importantly, T cells also pose the risk of pathogenic
responses if they are specific to self or transplant antigens and are not controlled by peripheral tolerance
mechanisms. The macrocomplexes that drive T cell activity are therefore interesting both from an engineering
standpoint, as they serve as an ideal framework upon which to design novel chimeric receptors for redirected T
cell therapy, and from a targeting standpoint for therapies aimed at mitigating T cell-mediated pathologies
when tolerance breaks down. This proposal will test the efficacy of using a novel 5-module chimeric antigen
receptor system (5MCAR), which has been engineered to operate according to the mechanistic principles that
govern the TCR-CD3-pMHC-CD4/CD8 macrocomplexes, to redirect CTLs to target pathogenic T cells. Our
goals are to: use 5MCAR-CTLs to eliminate pMHC-specific T cell populations, including pathogenic T cells, via
a surgical strike in order to induce tolerance in mouse models; and, engineer and test humanized 5MCARs in a
humanized mouse model system. When completed, the work will provide a blueprint for using 5MCAR-CTL
therapy to induce tolerance to defined pMHC and mitigate T cell-mediated pathologies.

## Key facts

- **NIH application ID:** 10247395
- **Project number:** 1R56AI148466-01A1
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Michael S Kuhns
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $777,783
- **Award type:** 1
- **Project period:** 2020-09-10 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247395

## Citation

> US National Institutes of Health, RePORTER application 10247395, Inducing Tolerance with 5-Module chimeric Antigen Receptor (5MCAR) T Cells (1R56AI148466-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10247395. Licensed CC0.

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