# Project 3:  Integrative approach tounderstanding the mechanism ofcostimulation

> **NIH NIH P01** · YALE UNIVERSITY · 2021 · $662,499

## Abstract

The immunoinhibitory receptors PD-1 and TIGIT play critical roles in regulating tolerance, and are key
mediators of T cell dysfunction in cancer and chronic infections. Anti-PD-1 antibody is now an FDA
approved therapy for cancer, while anti-TIGIT is a highly promising target for enhancing anti-tumor
immunity. While PD-1 blockade is having impressive therapeutic effects in some cancers, many
patients do not respond to single agent immunotherapy. With recent studies showing striking synergies
between the PD-1 and TIGIT pathways in regulating T cell dysfunction in vivo, combination therapies
are under consideration. Our lab along with our collaborators in this PPG have shown that PD-1:PD-L1
interactions regulate both the induction and maintenance of peripheral T cell tolerance, and that TIGIT
has T cell intrinsic inhibitory effects that regulate tolerance. However, little is known about the
mechanisms by which these inhibitory pathways work individually, and particularly in
combination, to inhibit T cell activation. The goal of Project 3 is to determine the interactions
between TIGIT and PD-1 in controlling CD4+ regulatory T cells (Treg) and CD4+ FoxP3— T cells,
and define the genetic circuits underlying these interactions. In the first aim, we will test the
hypothesis that interactions between TIGIT and PD-1 control Treg function and/or stability, and
synergize to have a dominant effect on CD4+ FoxP3- T cells, thereby controlling T cell tolerance. We will
examine how combinations of agonists or antagonists to PD-1 and TIGIT alter the function of Treg and
self reactive CD4+ FoxP3— T cells in vitro, as well as the pathogenicity of myelin-reactive CD4+ T cells
in vivo in the EAE model. We will use TIGIT/PD-1 double conditional knockout mice (cKO) to test
synergy within specific cell types. In the second aim, we will infer the transcriptional networks mediating
the actions of PD-1 and TIGIT in Tregs and CD4+ FoxP3— T cells, based on the dynamic profiles of
RNA expression in activated CD4+ FoxP3— T cells and Treg, and measurements of open chromatin by
ATAC-seq. Guided by this inferred transcriptional map, we will systematically perturb and test the
functions of candidate transcription factors in vitro during T cell activation or in vivo upon transfer of
MOG-specific T cells to induce EAE. The results of this proposal should provide critical insights into
how TIGIT and PD-1 interact to modulate T cell activation and tolerance. Furthermore, our results will
contribute directly to Projects 1 and 2 by providing explanations for the changes observed in T cell
functions in the absence of TIGIT (Project 1) and functional differences in T cells between MS patients
vs. malignant gliomas based on PD-1 and TIGIT expression and activity (Project 2). Improvements in
our functional and mechanistic understanding of costimulator and coinhibitor interactions should lead to
new therapeutic targets and strategies for reducing autoimmunity while increasing anti-tumor immu...

## Key facts

- **NIH application ID:** 10219110
- **Project number:** 5P01AI039671-24
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Arlene H. Sharpe
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $662,499
- **Award type:** 5
- **Project period:** 1997-09-01 → 2023-05-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219110

## Citation

> US National Institutes of Health, RePORTER application 10219110, Project 3:  Integrative approach tounderstanding the mechanism ofcostimulation (5P01AI039671-24). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10219110. Licensed CC0.

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