Frontiers in Molecular Neuroscience · Jul 16, 2026

Regulatory T cells in perioperative neurocognitive disorders: a systematic review with structured narrative synthesis from molecular mechanisms to clinical translation

By Zhu Y, Chai K, Chou C et al.

BACKGROUND: Perioperative neurocognitive disorders (PND), encompassing postoperative delirium and postoperative cognitive dysfunction, are common complications following anesthesia and surgery, particularly in elderly patients. Neuroinflammation has been identified as a central mechanism underlying PND; however, the contribution of adaptive immune regulation remains incompletely understood. Regulatory T cells (Tregs), as key modulators of immune homeostasis, have recently emerged as potential regulators of perioperative neuroinflammatory responses. OBJECTIVE: This review aimed to comprehensively evaluate current preclinical and clinical evidence regarding the role of regulatory T cells in the development of perioperative neurocognitive disorders, with a focus on molecular mechanisms and translational implications. METHODS: A systematic literature search was conducted in PubMed, PubMed Central, Web of Science, Scopus, Embase, the Cochrane Library, and ClinicalTrials.gov from inception to 17 May 2026. Original animal and human studies investigating Treg frequency, function, or modulation in relation to perioperative cognitive outcomes were included. Study selection followed PRISMA 2020 guidelines, and methodological quality was assessed using the SYRCLE risk-of-bias tool (animal studies) and the Newcastle-Ottawa Scale (clinical studies). RESULTS: The search identified 312 records, of which 10 studies met the inclusion criteria, comprising four animal studies and six clinical studies. Preclinical evidence consistently demonstrated that surgical trauma induces alterations in Treg frequency and suppressive function, particularly in aged models, contributing to exaggerated neuroinflammation, blood-brain barrier disruption, microglial activation, and cognitive impairment. Clinical studies revealed associations between perioperative Treg imbalance-often reflected by an increased Th17/Treg ratio-and the occurrence of postoperative cognitive decline. Moreover, immunomodulatory interventions such as dexmedetomidine were shown to partially preserve Treg balance and reduce the incidence of postoperative cognitive dysfunction, although dexmedetomidine's pleiotropic actions (sympatholysis, opioid-sparing, sedation-related stress reduction) preclude attribution of its cognitive benefit solely to Treg modulation. CONCLUSION: Current evidence supports a critical role for regulatory T cells in the pathophysiology of perioperative neurocognitive disorders. Treg dysfunction contributes to excessive neuroinflammation and cognitive decline after surgery, whereas restoration of Treg-mediated immune regulation confers neuroprotective effects. Targeting regulatory T cells represents a promising translational strategy for the prevention and management of PND, warranting further mechanistic studies and well-designed clinical trials.

doi.org/10.3389/fnmol.2026.1856316Open accessPubMed 42534995Mechanisms