# Project 1 - Modulation of Tolerance and Autoimmunity by Inhibitory Receptors

> **NIH NIH P01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $456,302

## Abstract

PROJECT SUMMARY
PD1 and LAG3 play critical roles in regulating T cell tolerance and autoimmunity. Combined genetic deficiency 
of PD1 and LAG3 in mice results in lethal systemic autoimmunity, demonstrating PD1/LAG3 synergies in 
tolerance. The goal of Project 1 is to determine mechanisms by which PD1 and LAG3 control Treg and selfreactive CD4+ FoxP3– T cells in tolerance and autoimmunity. These are issues of fundamental and clinical 
significance, as PD1 and LAG3 are key mediators of T cell exhaustion and promising therapeutic targets, and 
there is a growing appreciation of immune-related adverse events in cancer patients treated with checkpoint 
blockade. A deeper understanding of how PD1 and LAG3 work together to mediate tolerance may enable optimal
effective PD1 and LAG3 cancer therapies, while minimizing autoimmunity. In contrast to exacerbated EAE in 
Pdcd1–/– mice, our preliminary data show that mice lacking PD1 in Treg develop ameliorated EAE. Conversely,
LAG3 deletion in Treg increased EAE severity, while combined PD1/LAG3 deletion in Treg reduced EAE. These 
findings highlight the need to determine how PD1/LAG3 signals are integrated in different cell types to 
understand how perturbing these pathways impacts protective Treg and pathogenic self-reactive CD4+ FoxP3– T 
cells. Based on these data, we hypothesize that synergy between PD1 and LAG3 operates by cellular and 
molecular mechanisms that differ in Treg and CD4+ FoxP3– T cells to control pathogenic and protective responses 
during EAE initiation and progression. We will test this hypothesis by clinical, cellular, and molecular analyses of 
a) novel inducible knockout mice where PD1 and/or LAG3 can be temporally deleted only in Treg cells or only in 
CD4+ Foxp3– T cells and b) mice given PD1 and/or LAG3 blocking antibodies. We will evaluate select targets 
from our studies to define mechanisms by which PD1/LAG3 coordinate to control cell fate and function. Aim 1:
What cellular and molecular events are triggered in Treg and self-reactive CD4+ FoxP3– T cells by PD1/ LAG3 
deletion or blockade during EAE onset? We hypothesize that PD1/LAG3 interactions have distinct effects on Treg
vs. CD4+ FoxP3– T cells during EAE initiation. We will define how PD1 and/or LAG3 deletion affects self-reactive 
CD4+ Foxp3– T cell activation/differentiation and Treg activation/function, and integrated effects of LAG3/PD1 
blockade. Aim 2: What cellular and molecular events are triggered in Treg and self-reactive CD4+ Foxp3– effector
(Teff) cells by PD1/LAG3 deletion or blockade after EAE onset? We predict that PD1/LAG3 interactions may differ 
in initiation vs. effector phases of EAE, since PD1 can regulate T cell differentiation fates and effector responses. 
We will define how PD1 and/or LAG3 deletion impacts Teff and Treg cells and integrated effects of PD1/LAG3 
blockade. Project 1 will collaborate with Projects 2 and 3 to compare effects of PD1/LAG3 disruption in tolerance
and T cell exhaustion: C...

## Key facts

- **NIH application ID:** 10894776
- **Project number:** 5P01AI108545-10
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Arlene H. Sharpe
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $456,302
- **Award type:** 5
- **Project period:** 2015-05-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10894776

## Citation

> US National Institutes of Health, RePORTER application 10894776, Project 1 - Modulation of Tolerance and Autoimmunity by Inhibitory Receptors (5P01AI108545-10). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10894776. Licensed CC0.

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