Monday, May 19, 2025
5/19/2025
The Role of CD4+ Memory T cell Subtypes in Periodontal Disease Recurrence - 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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).