• Peiying Li, Leilei Mao, Xiangrong Liu, Yu Gan, Jing Zheng, Angus W Thomson, Yanqin Gao, Jun Chen, and Xiaoming Hu.
• From the State Key Laboratory of Medical Neurobiology and Institute of Brain Sciences, Department of Anesthesiology, Huashan Hospital, Fudan University, Shanghai, China (P.L., L.M., X.L., Y. Gao, J.C., X.H.); Center of Cerebrovascular Disease Research (P.L., L.M., Y. Gan, J.Z., J.C., X.H.) and Departments of Surgery and Immunology, Starzl Transplantation Institute (A.W.T.), University of Pittsburgh School of Medicine, PA; Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, PA (P.L., X.H.); and Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, People's Republic of China (X.L.).
• Stroke. 2014 Mar 1;45(3):857-64.

Background And PurposeOur recent research revealed that adoptively transferred regulatory T cells (Tregs) reduced acute ischemic brain injury by inhibiting neutrophil-derived matrix metalloproteinase-9 (MMP-9) and protecting against blood-brain barrier damage. The mechanisms underlying Treg interactions with neutrophils remain elusive. This study evaluates the contribution of program death 1-ligand 1 (PD-L1) to Treg-mediated neutrophil inhibition and neuroprotection after cerebral ischemia.MethodsIn vitro experiments were performed using a transwell system or a coculture system allowing cell-to-cell contact. Focal cerebral ischemia was induced in mice for 60 minutes. Tregs (2×10(6)) isolated from donor animals (wild-type or PD-L1-/-) were intravenously injected into ischemic recipients 2 hours after middle cerebral artery occlusion (MCAO). MMP-9 production, blood-brain barrier permeability, and brain infarct were assessed at 1 or 3 days after MCAO.ResultsIn vitro experiments reveal that Treg-mediated inhibition of neutrophil MMP-9 required direct cell-to-cell contact. The suppression of MMP-9 was abolished when Tregs were pretreated with PD-L1 neutralizing antibodies or when neutrophils were pretreated with PD-1 antibodies. In vivo studies confirmed that intravenous administration of Tregs pretreated with PD-L1 antibodies or Tregs isolated from PD-L1-deficient mice failed to inhibit MMP-9 production by blood neutrophils 1 day after 60 minutes MCAO. Furthermore, the blood-brain barrier damage after MCAO was greatly ameliorated in PD-L1-competent Treg-treated mice but not in PD-L1-compromised Treg-treated mice. Consequently, PD-L1 dysfunction abolished Treg-mediated brain protection and neurological improvements 3 days after MCAO.ConclusionsPD-L1 plays an essential role in the neuroprotection afforded by Tregs against cerebral ischemia by mediating the suppressive effect of Tregs on neutrophil-derived MMP-9.

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