# Wnt3a is a central regulator for P. gingivalis-mediated expression of PD-L1 and suppression of CD8+ T cell activity

> **NIH NIH R21** · VIRGINIA COMMONWEALTH UNIVERSITY · 2022 · $232,875

## Abstract

Abstract
 Blockade of program death ligand-1 (PD-L1) is demonstrating remarkable clinical outcomes for patients
with cancer or chronic infection through reinvigorating exhausted CD8+ T cell responses. However, only a small
portion of patients can respond well to this treatment, indicating a dire need for an in-depth understanding of the
function and regulatory mechanisms of PD-L1. Recent breakthrough findings revealed that expression of PD-L1
on dendritic cells (DCs) is critical for the efficacy of PD-L1/PD-1 blockade immunotherapy. Porphyromonas
gingivalis (Pg) is a causative agent of chronic periodontal inflammation and tissue damages. Infection with Pg
was reported to aggravate cancer progression and promote PD-L1 expression in tumor cells. However, if and
how Pg infection promotes expression of PD-L1 on DCs and its possible effect on CD8+ T cell activity
remain entirely unknown. Thus, it is tempting to identify novel immune signaling modulators that can
regulate expression of PD-L1 and impact cytotoxic T cell activity, with a long-term goal of restoring the immune
system function in surveillance and elimination of invaded organisms and cancer cells. Our recent studies
demonstrated that Pg infection robustly increases expression of Wnt (Winglesss and Int-1) 3a in innate immune
cells and Wnt3a negatively regulates the intensity of innate immune responses. Our preliminary data suggest
that Pg infection (i) significantly enhances PD-L1 expression on BMDCs and impairs cytotoxicity of allogenic
antigen-specific CD8+ T cells; (ii) remarkably enhances expression of Wnt3a, and inhibition of Wnt3a reduces
expression of PD-L1 on BMDCs; and (iii) leads to an increase of Yes-associated protein 1(YAP) and WW-
domain-containing transcription regulator-1(TAZ) expression but a decrease of an upstream kinase
phosphorylation in DCs. Since YAP/TAZ was shown to associate with PD-L1 expression and interact with Wnt3a
signaling in other contexts, we thus hypothesize that Wnt3a is a critical immunomodulator that promotes
PD-L1 expression and suppresses CD8+ T cell activity upon stimulation with Pg by regulating activation
of YAP/TAZ signaling and its downstream transcriptional enhancer factor (TEA)-domain family of DNA-
binding factor 1 (TEAD1). We will demonstrate this hypothesis with two specific aims: (1): Establish the role
of Wnt3a as an endogenous regulator of the Pg-induced PD-L1 and impairment of CD8+ T cell activity;
(2) Establish if Wnt3a promotes Pg-induced PD-L1 expression and impairment of CD8+ T cell activity via
modifying the activity of YAP/TAZ and its downstream TEAD1. Successful completion of this project will (i)
maps out a novel and potentially critical signaling pathway (Wnt3a-YAP/TAZ-TEAD1) and identifies more
interventional targets in PD-L1 expression; and (ii) greatly aids in understanding the regulatory mechanism
that Pg infection impairs CD8+ T cell cytotoxicity, which will pave the way for the development of innovative
immunoregulatory the...

## Key facts

- **NIH application ID:** 10592576
- **Project number:** 1R21DE031376-01A1
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Huizhi Wang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $232,875
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10592576

## Citation

> US National Institutes of Health, RePORTER application 10592576, Wnt3a is a central regulator for P. gingivalis-mediated expression of PD-L1 and suppression of CD8+ T cell activity (1R21DE031376-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10592576. Licensed CC0.

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