# The Role of CD4+ Memory T cell Subtypes in Periodontal Disease Recurrence

> **NIH NIH K99** · ADA FORSYTH INSTITUTE, INC. · 2024 · $162,108

## Abstract

Project Summary
The recurrence of periodontal disease (PD) is a poorly immunologically defined or therapeutically targeted
clinical challenge. Uncovering the homeostatic and pathogenic potential of long-term immune cells in
periodontal tissues is crucial to revealing the cellular drivers of PD recurrence. This proposal focuses on
an overlooked periodontal-associated cellular compartment, CD4+ T memory cells (TM), which can readily
recognize microbial antigens for a quick and robust response. For this purpose, we will utilize a newly
characterized murine model of recurrent PD and a method for gingival T-cell enrichment. In this model,
time is a critical variable for recognizing disease initiation, resolution, and recurrence. By establishing this
model, we will be able to define a “recovered” baseline instead of a “healthy” baseline state, which is more
clinically accurate. Also, it allows defining how multiple relapse episodes incrementally impact the complex
periodontally-associated immune network. The preliminary studies revealed that CD4+ TM developed in the
gingiva soon after birth due to increasing environmental antigenic exposure. While the mice fully recovered
from ligature-induced PD, the bone loss rate accelerated during PD recurrence. Most intriguingly, CD4+ TM
subtypes are enriched in the gingiva during PD recurrence. Gingival CD4+ tissue-resident memory cells
induced bone loss when circulating T cell infiltration was inhibited. Based on these findings, we will test the
hypothesis that the PD-induced generation and persistence of CD4+ TM subtypes determine PD
recurrence. Thus, targeted depletion of these cells by inhibiting metabolic checkpoints will enhance
immune-regulatory responses and inhibit PD recurrence. There are three interconnected but independent
Aims: 1) To identify the spatiotemporal development of CD4+ TM cells in periodontal tissues. Here, the
focus will be on understanding the constitutive and pathologic generation of CD4+ TM cells to determine
their roles in the gingival immune landscape. 2) To elucidate PD-induced CD4+ TM pathogenicity. Here, we
will evaluate which CD4+ TM subtypes retain pro-inflammatory and osteoclastogenic programming after
PD. We will make transcriptomic comparisons between CD4+ TM subtypes and assess the findings with ex
vivo functional assays to validate their pathogenic potential. 3) To develop an intervention strategy for CD4+
TM depletion to prevent PD recurrence. Here, we will employ a metabolic-based strategy to selectively
deplete PD-induced CD4+ TM and enhance regulatory T cells enrichment to prevent PD recurrence. The
independence award (PAR-22-041) will foster my independent research growth and allow me to accomplish
my long-term career goal to become a productive, independent translational scientist in periodontology and
related fields focused on chronic diseases’ recurrence.

## Key facts

- **NIH application ID:** 10884509
- **Project number:** 5K99DE032704-02
- **Recipient organization:** ADA FORSYTH INSTITUTE, INC.
- **Principal Investigator:** Carla Andrea Alvarez Rivas
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $162,108
- **Award type:** 5
- **Project period:** 2023-08-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10884509

## Citation

> US National Institutes of Health, RePORTER application 10884509, The Role of CD4+ Memory T cell Subtypes in Periodontal Disease Recurrence (5K99DE032704-02). Retrieved via AI Analytics 2026-06-23 from https://api.ai-analytics.org/grant/nih/10884509. Licensed CC0.

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