# Project 1:  Role of TIGIT/CD226 pathway in regulating T cell responses

> **NIH NIH P01** · YALE UNIVERSITY · 2021 · $602,000

## Abstract

PROJECT SUMMARY/ABSTRACT – PROJECT 1
The CD226/TIGIT pathway is a novel co-stimulatory/co-inhibitory pathway that closely parallels the
CD28/CTLA-4 pathway. Similar to CD28 and CTLA-4, CD226 and TIGIT share ligands (CD112 and CD155)
and ligand engagement of CD226 co-stimulates T cell activation while engagement of TIGIT inhibits T cell
responses. Over the last few years, TIGIT has emerged as an important co-inhibitory receptor. While initial
experiments indicated that TIGIT inhibits T cell responses indirectly by promoting tolerogenic phenotype in
dendritic cells, we, and others, have shown that TIGIT has T cell-intrinsic inhibitory functions. We have now
found that TIGIT is co-expressed with other co-inhibitory receptors (PD-1,Tim-3,Lag-3) on CD8+ T cells that
exhibit dysfunctional/exhausted phenotype in chronic diseases such as cancer and chronic viral infection.
Importantly, we find that expression of TIGIT marks the most dysfunctional subset of CD8+ T cells in these
conditions, thus raising the important issue of how TIGIT co-operates with other inhibitory receptors to drive
severe dysfunctional phenotype in effector T cells. In addition to its role in effector T cells, we have recently
identified that TIGIT marks a distinct subset of regulatory T cells (Treg) that exhibit heightened expression of
known Treg effector molecules and increased suppressive capacity. Importantly, we find that TIGIT+ Treg are
highly enriched in inflamed tissues and that they exhibit specialized function; selectively suppressing pro-
inflammatory Th1/Th17 responses while sparing Th2 responses. However, how TIGIT may function in CD8+ T
cells to dampen their responses while in Treg function to direct specialized Treg function is not known.
Given the data supporting important roles for TIGIT in regulating effector T cells and Treg, it is surprising that
nothing is known regarding the molecular signals that induce TIGIT expression. Our preliminary data indicate
that the immunomodulatory cytokine IL-27 induces TIGIT expression both in vitro and in vivo. We have now
leveraged this information to identify candidate transcription factors that are downstream of IL-27 and may
drive TIGIT expression in effector T cells.
Based on our data, we hypothesize that TIGIT has a dual role in regulating T cell responses: 1) TIGIT co-
operates with other co-inhibitory molecules to regulate effector T cell phenotype and 2) TIGIT drives highly
active and specialized Treg phenotype in tissue. We have generated a number of tools including agonist and
antagonist antibodies and conditional knock-out mice to study the function of this emerging pathway in the
regulation of T cell responses. Our specific aims are:
1) Dissect the T cell intrinsic and extrinsic roles of TIGIT in regulating T cell activation and dysfunction
2) Determine the role of TIGIT in directing Treg function in inflammatory conditions

## Key facts

- **NIH application ID:** 10219112
- **Project number:** 5P01AI039671-24
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** VIJAY K. KUCHROO
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $602,000
- **Award type:** 5
- **Project period:** 1997-09-01 → 2023-05-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219112

## Citation

> US National Institutes of Health, RePORTER application 10219112, Project 1:  Role of TIGIT/CD226 pathway in regulating T cell responses (5P01AI039671-24). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10219112. Licensed CC0.

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