# Costimulatory Mechanisms of Autoimmunity

> **NIH NIH P01** · YALE UNIVERSITY · 2020 · $2,538,330

## Abstract

Immune function is highly dependent upon costimulatory signals where their role has become apparent in the
study of tumor infiltrating lymphocytes; expression of PD-L1 can engage PD-1 leading to T cell dysfunction with
unchecked tumor growth. Similarly, there is a central role of T cell costimulatory signals in autoimmune disease
particularly with activation of autoreactive T cells and induction of epitope spreading which has become evident
with the emergence of autoimmune toxicities after blockade of coinhibitory signals in patients with cancer.
Moreover, genetic variants identified in the costimulatory receptor CD226, and its ligand CD155 (shared with
TIGIT) are strongly associated with risk of MS, indicating that this pathway maybe central in MS autoimmunity.
These studies have led us to more deeply examine the TIGIT/CD226/CD155 and PD-1/PD-L1 pathways in
autoimmunity versus their opposing roles in cancer followed with building regulatory networks in T cells by first
analyzing interactions between these costimulatory pathways pairwise and then integrating co-stimulatory/co-
inhibitory T cell signals. The uniqueness of this grant resides in 3 areas: 1) in vitro and in vivo model systems
to evaluate costimulation in autoimmune disease; 2) availability of unique reagents to inhibit costimulation; and
3) PPG investigators to translate basic research to the clinic. In Project 1, we will examine the role of
TIGIT/CD226 pathway in regulating T cell responses, investigating the hypothesis that TIGIT has dual roles in
regulating T cell responses, cooperating with other co-inhibitory molecules to regulate effector T cell and Treg
responses. We will dissect the roles of TIGIT in effector T cells and Treg in experimental inflammatory
conditions. In Project 2, we hypothesize that loss of TIGIT expression or function in MS drives autoimmune
responses, while in tumors, increased TIGIT expression or signaling allows tumors to escape immune
surveillance. We will determine the role of TIGIT/CD226 in regulating CD4+ T cell activation in human
inflammatory disorders. Secondly, we will investigate the role of TIGIT/CD226 on the function of Treg
populations in MS, hypothesizing there are defects in the function of TIGIT+ Tregs in MS patients inducing
dysfunctional Th1-like Tregs. In Project 3, we will use an integrative approach to understand mechanisms of
costimulation. Our goal is to define genetic circuits underlying interactions between the costimulatory
coinhibitory receptors PD-1 and TIGIT. We will determine how these costimulatory and coinhibitory receptors
interact to regulate CD4+ T cell functions, and from that infer a transcriptional network mediating T cell function.
Finally, we will test the roles of candidate regulators in the network underlying the activities of co-stimulators
and co-inhibitors in CD4+ T cells. These studies will provide mechanistic insights into how TIGIT and PD1 exert
their critical immunoregulatory functions in regulating T cell t...

## Key facts

- **NIH application ID:** 9986616
- **Project number:** 5P01AI039671-23
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** David A. Hafler
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,538,330
- **Award type:** 5
- **Project period:** 1997-09-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986616

## Citation

> US National Institutes of Health, RePORTER application 9986616, Costimulatory Mechanisms of Autoimmunity (5P01AI039671-23). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9986616. Licensed CC0.

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