ObjectiveRecent evidence suggests that functional deficiency in regulatory T cells (Tregs), an innate immunomodulator, exacerbates brain damage after cerebral ischemia. We therefore evaluated the effect of Treg transfer in rodent models of ischemic stroke and further investigated the mechanism underlying Treg-afforded neuroprotection. MethodsWe examined the therapeutic potential of Tregs and the mechanisms of neuroprotection in vivo in 2 rodent models of ischemic stroke and in vitro in Treg-neutrophil cocultures using a combined approach including cell-specific depletion, gene knockout mice, and bone marrow chimeras. ResultsSystemic administration of purified Tregs at 2, 6, or even 24 hours after middle cerebral artery occlusion resulted in a marked reduction of brain infarct and prolonged improvement of neurological functions lasting out to 4 weeks. Treg-afforded neuroprotection was accompanied by attenuated blood-brain barrier (BBB) disruption during early stages of ischemia, decreased cerebral inflammation, and reduced infiltration of peripheral inflammatory cells into the lesioned brain. Surprisingly, Tregs exerted early neuroprotection without penetrating into the brain parenchyma or inhibiting the activation of residential microglia. Rather, both in vivo and in vitro studies demonstrated that Tregs suppressed peripheral neutrophil-derived matrix metallopeptidase-9 production, thus preventing proteolytic damage of the BBB. In addition to its potent central neuroprotection, Treg treatment was shown to ameliorate poststroke lymphopenia, suggesting a beneficial effect on immune status. InterpretationOur study suggests that Treg adoptive therapy is a novel and potent cell-based therapy targeting poststroke inflammatory dysregulation and neurovascular disruption. Ann Neurol 2013;74:458-471
[1]Fudan Univ, Huashan Hosp, Dept Anesthesiol, State Key Lab Med Neurobiol, Shanghai 200433, Peoples R China.
[2]Fudan Univ, Inst Brain Sci, Shanghai 200433, Peoples R China.
[3]Univ Pittsburgh, Sch Med, Ctr Cerebrovasc Dis Res, Pittsburgh, PA USA.
[4]Shandong Univ, Affiliated Hosp, Taishan Med Coll, Dept Neurol, Tai An, Shandong, Peoples R China.
[5]Shandong Univ, Affiliated Hosp, Taishan Med Coll, Key Lab Cerebral Microcirculat, Tai An, Shandong, Peoples R China.
[6]Univ Pittsburgh, Sch Med, Dept Immunol, Pittsburgh, PA USA.
[7]Univ Pittsburgh, Sch Med, Dept Surg, Starzl Transplantat Inst, Pittsburgh, PA USA.
[8]Vet Affairs Pittsburgh Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA.
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