# Enhancing the TCR-induced Response of HLA-E-restricted Regulatory CD8 T Cells to Promote Allograft Tolerance

> **NIH NIH K08** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $195,126

## Abstract

Abstract
We pioneered a novel regulatory CD8 T subset (CD8 Treg) that promotes transplant tolerance by suppressing
pathogenic CD4 T cells. CD8 Tregs use semi-variant TCRs that allow the selective killing of alloreactive CD4 T
cells via recognizing the surface class-Ib MHC molecules (Qa-1 in mice and HLA-E in humans). These CD8
Tregs express distinctive co-signaling receptors, including inhibitory Killer Ig-like receptor (iKIR), a checkpoint
that constrains the uncontrolled response of CD8 Tregs. The overall goal of this project is to leverage the
expertise we gained through the study of mice CD8 Tregs to develop clinically relevant CD8 Treg
immunotherapy. Our central hypothesis is that HLA-E-binding superagonists and iKIR inhibitors can
selectively mobilize human CD8 Tregs and promote allograft tolerance. In Aim 1, I will exploit the semi-
variant nature of HLA-E-restricted TCRs to develop a tolerogenic superagonist that specifically stimulates CD8
Tregs. This will be achieved by defining a dominant TCR used by human CD8 Tregs and reconstructing this
TCR to screen for a potent inducer from a peptide-HLA-E presenting yeast library. Using a kidney transplant
recipient's PBMCs, I will validate the efficacy of selected superagonists inducing CD8 Treg cytotoxicity against
alloreactive CD4 T cells. In Aim 2, I will study the mechanism of iKIR controlling the CD8 Treg response. I will
analyze the phosphorylation status of TCR signaling molecules and examine the change in CD8 Treg effector
capacity upon blocking the iKIR, in vitro. To investigate the role of iKIR expressed by human CD8 Tregs in
vivo, I will use a novel humanized kidney organoid transplant model we established; I will analyze the
activation of CD8 Tregs, suppression of alloreactive CD4 T cells, and prolongation of kidney organoid allograft
survival when humanized hosts are treated with an iKIR-inhibiting antibody.
Successful completion of the project can transform therapeutic strategies to achieve tolerance by suggesting a
human CD8 Treg vaccine, CD8 Treg-specific checkpoints, and a novel humanized mice model that allows
studying CD8 Treg immunotherapy, in vivo. The K08 award is necessary and sufficient to advance my niche in
catalyzing preclinical discoveries into phase-1 trials and to pursue my long-term goal of developing clinically
relevant personalized tolerogenic therapies.

## Key facts

- **NIH application ID:** 10865505
- **Project number:** 1K08AI182491-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** John Yongjoon Choi
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $195,126
- **Award type:** 1
- **Project period:** 2024-06-14 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10865505

## Citation

> US National Institutes of Health, RePORTER application 10865505, Enhancing the TCR-induced Response of HLA-E-restricted Regulatory CD8 T Cells to Promote Allograft Tolerance (1K08AI182491-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10865505. Licensed CC0.

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