Ligature-induced periodontitis in mice potentially accelerates CD4⁺ T-cell senescence and exacerbates rheumatoid arthritis

INTRODUCTION: Aging impairs immunity, sustains chronic inflammation, and enhances autoimmunity-a process termed "immunosenescence" that contributes to the pathogenesis of type 2 diabetes and rheumatoid arthritis (RA). Post-pubertal thymic involution depletes naïve T-cell pool, promoting the emergence of senescent CD4⁺ T cells. To maintain T-cell homeostasis, these cells undergo extensive homeostatic proliferation, eventually reaching their replicative limit. Characterized by PD-1 and CD153 expression, these senescent cells exhibit diminished proliferative capacity and an enhanced senescence-associated secretory phenotype (SASP). While chronic periodontitis, which typically affects middle-aged individuals, is known to influence systemic conditions like RA (periodontal medicine), the underlying mechanisms remain elusive. This study investigates whether periodontitis accelerates CD4⁺ T-cell senescence and its subsequent impact on systemic disease. METHODS: BALB/c mice (5-42 weeks old) underwent silk ligation of the maxillary second molars to induce experimental periodontitis (LIP). Splenic CD4⁺ T cells were isolated and stimulated with IL-2, and anti-TCRβ/CD28 antibodies for 1-3 days to promote T-cell activation and expansion. RESULTS: Although the frequency of PD-1⁺CD153⁺ cells did not differ significantly between the LIP and control groups in vivo, the LIP group showed significantly higher proportion of these double-positive cells following in vitro stimulation, peaking at 18 weeks. The LIP group further exhibited elevated SASP cytokine levels, an increased prevalence of senescence-associated β-galactosidase (SA β-gal)-positive cells and a reduced proportion of cells in the S phase, indicating accelerated senescence. RNA-seq analysis revealed numerous differentially expressed genes (DEGs) related to senescence in unstimulated helper T cells from the LIP group. Finally, adoptive transfer of CD4⁺ T cells from the LIP group into nude mice exacerbated collagen antibody-induced arthritis (CAIA). CONCLUSIONS: These findings suggest that severe periodontal inflammation induces a "senescence-primed" status in the helper T cells. These senescent cells may enter systemic circulation and exacerbate RA, highlighting a novel cellular mechanism linking periodontitis to systemic disease.