# Project 2: Elucidating how TIGIT agonists regulate CNS autoimmunity exacerbated by PD-1 blockade

> **NIH NIH P01** · YALE UNIVERSITY · 2023 · $631,388

## Abstract

The immunoinhibitory receptors PD-1 and TIGIT play critical roles in regulating tolerance and are key mediators
of T cell dysfunction in cancer. We, along with our collaborators in this PPG, have shown that PD-1:PD-L1
interactions regulate peripheral T cell tolerance and TIGIT has T cell-intrinsic inhibitory effects that mediate
regulatory T (Treg) cell function. Based on our new preliminary data showing PD-1 blockade increases the
frequency of TIGIT+ Treg cells and data of Project 3 showing that TIGIT agonist reversed in vitro defects of Treg
function in MS, we tested if TIGIT agonism could control pathogenic T cells and ameliorate autoimmunity
exacerbated by PD-1 blockade using the EAE model. Remarkably, TIGIT agonist mAb diminished EAE severity
in mice given anti-PD-1 blocking mAb to a greater extent than TIGIT agonism alone. Importantly, TIGIT agonism
combined with PD-1 blockade did not impair efficacy of PD-1 blockade in controlling tumors, suggesting TIGIT
as a potential target for treating immune-related adverse events (irAEs) associated with PD-1 blockade therapy.
The goal of Project 2 is to determine how interactions between the TIGIT/CD155 and PD-1/PD-L1
pathways control CD4+ Treg and CD4+ FoxP3— T cells, and define the cellular and molecular circuits
underlying these interactions. In Aim 1, we will test the hypothesis that cellular and molecular interactions
between PD-1 and TIGIT control Treg and CD4+ FoxP3—T cells to regulate autoimmunity. We will use novel tools
and approaches developed by PPG investigators, including TIGIT agonist antibodies, TIGIT and PD-1
conditional knockout (KO) mice that restrict deletion to specific T cell types, high-dimensional cytometry, single-
cell RNA sequencing (scRNAseq), spatial transcriptomics and gene perturbation approaches to interrogate
cellular and molecular mechanisms. In Aim 2, we will test the hypothesis that interactions between CD155 and
PD-L1 on APC and tumors balance Treg and T effector cell functions to regulate tissue inflammation. We will
evaluate functional interactions between CD155 and PD-L1, focusing on their cell-intrinsic functions in DC and
tumor cells, and cell-extrinsic effects on Treg and CD4+ FoxP3— T cells, using CD155 and PD-L1 conditional KO
mice that restrict deletion to DC and tumor cells lacking CD155 and/or PD-L1 or only their cytoplasmic domains,
and similar approaches as in Aim 1. Our results will provide critical insights into unique and overlapping nodes
by which PD-1/PD-L1 and TIGIT/CD155 interact to modulate Treg and CD4+FoxP3— cells to regulate T cell
tolerance. Moreover, our results will contribute directly to Projects 1 and 3 by providing insight into bidirectional
interactions between TIGIT and CD155 (Project 1) and functional differences in T cells from patients with MS or
malignant gliomas based on PD-1/PD-L1 and TIGIT/CD155 expression and activity (Project 3). Understanding
mechanisms of TIGIT/CD155 and PD-1/PD-L1 interactions should enable design of new...

## Key facts

- **NIH application ID:** 10643434
- **Project number:** 2P01AI039671-25
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Arlene H. Sharpe
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $631,388
- **Award type:** 2
- **Project period:** 1997-09-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10643434

## Citation

> US National Institutes of Health, RePORTER application 10643434, Project 2: Elucidating how TIGIT agonists regulate CNS autoimmunity exacerbated by PD-1 blockade (2P01AI039671-25). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10643434. Licensed CC0.

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