The evolving role of regulatory T cells in Sjögren's disease pathogenesis and the promise of Treg‐based therapies: A comprehensive review

Abstract Sjögren's disease (SjD) is a chronic systemic autoimmune disorder characterised by exocrine gland dysfunction and diverse systemic manifestations. While both innate and adaptive immune dysregulation contribute to pathogenesis, growing evidence highlights a central role for regulatory T cells (Tregs) in maintaining immune tolerance and preventing autoimmunity. In SjD, Tregs display numerical reduction, impaired expansion, and functional instability, compromising their ability to suppress autoreactive lymphocytes. Moreover, the inflammatory milieu promotes Treg plasticity, with loss of Foxp3 expression and conversion into pro‐inflammatory “ex‐Tregs”, further amplifying tissue damage. A key pathogenic hallmark is the disturbed Th17/Treg axis, skewed toward Th17 dominance and driven by cytokines such as IL‐17, IL‐6, and IL‐23, exacerbating glandular destruction. Correlations between Treg profiles, systemic disease activity, and clinical outcomes suggest their potential utility as biomarkers for disease monitoring and therapeutic stratification. Emerging therapeutic approaches aim to restore Treg‐mediated tolerance. Low‐dose interleukin‐2 therapy selectively expands functional Tregs, with promising clinical trial outcomes in SjD and related autoimmune diseases. Additional strategies include modulation of gut microbiota to enhance mucosal Treg function, adoptive transfer of ex vivo expanded or engineered Tregs, and cell‐free approaches using Treg‐derived exosomes. Despite these advances, challenges persist, particularly regarding Treg instability in inflammatory environments and the difficulty of generating antigen‐specific therapies. Targeting Tregs represents a paradigm shift from broad immunosuppression toward precision immune restoration in SjD. By reinforcing the body's natural regulatory networks, Treg‐based interventions hold promise for durable disease control and improved patient outcomes.