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

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. Project Number: 5R00DE032704-04 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Carla Alvarez Rivas | Institution: STATE UNIVERSITY OF NEW YORK AT BUFFALO, AMHERST, NY | Award Amount: $247,190 | Activity Code: R00 | Study Section: NSS View on NIH RePORTER: https://reporter.nih.gov/project-details/11319752