# Costimulatory Mechanisms of Autoimmunity

> **NIH NIH P01** · YALE UNIVERSITY · 2024 · $2,514,298

## Abstract

Our PPG renewal is driven by the fundamental and therapeutic importance of PD-1 and TIGIT in regulating T
cell tolerance and T cell dysfunction in cancer and autoimmunity and builds on significant progress we have
made in our previous grant cycle. Our productivity is highlighted by 43 primary publications and 27 reviews.
Working together, we previously demonstrated that PD-1:PD-L1 interactions regulate T cell tolerance while TIGIT
has T cell intrinsic inhibitory effects that mediate Treg function. Based on new preliminary data showing PD-1
deletion increases the frequency of TIGIT+ Tregs and TIGIT agonist reversed in vitro defects of Treg function in
MS, we examined if TIGIT agonism could control pathogenic T cells and ameliorate autoimmunity exacerbated
by PD-1 blockade using the EAE model. Remarkably, TIGIT agonist diminished EAE severity in mice given anti-
PD-1 blocking mAb while not impairing PD-1 efficacy in controlling tumors. Thus, TIGIT is a potential target for
treating immune-related adverse events (irAEs) associated with PD-1 blockade therapy. We also found that both
PD-L1 and CD155 are upregulated in CNS myeloid cells in states of chronic neurological inflammation and the
TIGIT expressed on Tregs promotes oncogenesis and immune evasion by directly signaling via its ligand CD155
expressed on tumor cells. These discoveries demonstrate ongoing synergy within our PPG with sharing of
unpublished data that have inspired the hypotheses and experiments which drive the focus of this application.
The hypothesis underlying this PPG is that bi-directional signaling through TIGIT/CD155 and PD-1/PD-
L1 balance Treg and T effector function and regulate tissue inflammation in autoimmunity and cancer.
Our PPG will consist of three highly integrated and interactive Projects, supported by three Cores. Project 1 will
elucidate bidirectional interactions between TIGIT and CD155 in autoimmunity and cancer. Project 2 will
determine cellular and molecular underpinnings of TIGIT/CD155 and PD-1/PD-L1 interactions that regulate Treg
and CD4+Foxp3– function. Project 3 will investigate the roles of TIGIT/CD155 and PD-1/PD-L1 in regulating
human CNS inflammation and cancer. Core A (Hafler) will provide administrative and scientific coordination,
Core B (Sharpe/Kuchroo) will provide novel mouse strains and gene perturbation technologies, and Core C
(Zhang/Fan) will provide spatial multi-omics and data integration of all three projects. Our major goals are to: 1)
deeply examine the TIGIT/CD226-CD155 and PD-1/PD-L1 pathways in autoimmunity in relationship to their
opposing roles in cancer; 2) identify the cellular and molecular circuits underlying interactions between the
TIGIT/CD155 and PD-1/PD-L1 pathways to regulate Treg and T effector cell function; 3) determine how reverse
signaling of CD155/PD-L1 alone or in combination into myeloid cells and tumors regulates their function; 4)
develop novel strategies for treating autoimmunity and irAEs. These Projects exempl...

## Key facts

- **NIH application ID:** 10839288
- **Project number:** 5P01AI039671-26
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** David A. Hafler
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,514,298
- **Award type:** 5
- **Project period:** 1997-09-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10839288

## Citation

> US National Institutes of Health, RePORTER application 10839288, Costimulatory Mechanisms of Autoimmunity (5P01AI039671-26). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10839288. Licensed CC0.

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