The Role of Regulatory T Cells in Periodontitis With or Without Systemic Diseases: A Systematic Review

Periodontitis is a chronic immune-mediated inflammatory disease of the oral cavity, frequently linked to systemic conditions through complex immunological pathways. Regulatory T lymphocytes (Tregs) are pivotal in maintaining immune homeostasis by producing anti-inflammatory mediators and enforcing self-tolerance. Recent research has highlighted their role in inflammatory, immune-mediated, and neoplastic diseases. This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, exploring the role of Tregs in periodontitis, including patients with comorbidities such as type 2 diabetes mellitus, rheumatoid arthritis, atherosclerosis, and cancer, with a focus on cytokine profile alterations and therapeutic implications of Treg modulation. A systematic search of PubMed, Scopus, Web of Science, and Cochrane from January 2015 to August 2025 using "periodontitis" and "Tregs" or "regulatory T cells" yielded 20 studies. Available evidence suggests alterations in the balance between immunomodulatory Tregs and pro-inflammatory Th17 lymphocytes, together with changes in related cytokine profiles compared with healthy controls. Changes in Treg-related immune markers have also been reported following periodontal interventions; however, these findings do not establish a causal role for Treg modulation or support Treg-targeted therapies in current clinical practice. Well-designed prospective studies and, where appropriate, randomized controlled trials are required to strengthen causal and therapeutic inference.