# Immunologic mechanisms that prevent autoimmunity

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2021 · $409,031

## Abstract

PROJECT SUMMARY
 We have identified a subset of CD8+ cells programmed to inhibit activation and expansion of helper T
(TH) cells through recognition of the class Ib MHC molecule Qa-1 (HLA-E in man). Mice that express a Qa-1
point mutation that disrupts binding of Qa-1 to the TCR/CD8 co-receptor of Treg develop dysregulated TFH
responses and die of systemic autoimmune disease 9-12m after birth. Regulatory activity is mediated by <5%
of CD8 T cells that express a diagnostic triad of surface receptors. We have also shown that the Helios
transcription factor (TF) stabilizes the CD8 Treg genetic program and have recently identified the highly
restricted T-cell receptor (TCR) repertoire that may mediate Ag-specific recognition by CD8 Treg. We use
these findings to trace the development of this regulatory CD8 lineage and apply these insights towards
development of novel therapeutic approaches to autoimmune disease.
 We propose here to test the premise that Qa-1-restricted CD8 Treg represent a unique regulatory
lineage of CD8 cells that express a Helios-dependent genetic program and a restricted set of TCR specific for
Qa-1/HA-E-associated self-peptides. In Aim 1, we will define the contribution of the TCR to intrathymic CD8
Treg selection and differentiation using Ag-specific TCR knock-in (KI) and retrogenic mice that express a TCR
specific for Qa-1-restricted self-peptides. This analysis will also allow dissection of the molecular requirements
for thymic selection and differentiation of class Ib MHC-dependent CD8+ Treg. Single-cell transcriptome
analysis will be used to define the relationship between TCR specificity for Qa-1–peptide ligands and shaping
of the lineage-specific genetic program of Ag-specific CD8 Treg. In Aim 2, we will define the contribution of the
Helios TF to thymic and post-thymic differentiation of CD8 Treg. This approach will entail measurement of the
impact of specific deletion of Helios at defined stages of Ag-specific CD8 Treg differentiation.
 The results from these studies and SA1 will provide a foundation for investigation of the interaction
between Ag-specific CD8 Treg and target cells in disease settings (Aim 3). Here we will define the inhibitory
interaction between Ag-specific CD8+ Treg and its target cells. Since Helios-dependent expression of NKG2D
costimulatory receptors may be essential to CD8 Treg signaling, we will characterize the contribution of this
costimulatory receptor to CD8 Treg activation by stress-associated Qa-1–Hsp60 and NKG2D ligands (NKG2D-
L). Insight into this interaction will be applied to the design of nanoparticle-based therapeutic approaches to
autoimmune disease.

## Key facts

- **NIH application ID:** 10084244
- **Project number:** 5R01AI037562-24
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** HARVEY CANTOR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $409,031
- **Award type:** 5
- **Project period:** 1996-07-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10084244

## Citation

> US National Institutes of Health, RePORTER application 10084244, Immunologic mechanisms that prevent autoimmunity (5R01AI037562-24). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10084244. Licensed CC0.

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