Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261, USA.
Immunity. 2021 Jul 13;54(7):1527-1542.e8. doi: 10.1016/j.immuni.2021.04.022. Epub 2021 May 19.
The precise mechanisms underlying the beneficial effects of regulatory T (Treg) cells on long-term tissue repair remain elusive. Here, using single-cell RNA sequencing and flow cytometry, we found that Treg cells infiltrated the brain 1 to 5 weeks after experimental stroke in mice. Selective depletion of Treg cells diminished oligodendrogenesis, white matter repair, and functional recovery after stroke. Transcriptomic analyses revealed potent immunomodulatory effects of brain-infiltrating Treg cells on other immune cells, including monocyte-lineage cells. Microglia depletion, but not T cell lymphopenia, mitigated the beneficial effects of transferred Treg cells on white matter regeneration. Mechanistically, Treg cell-derived osteopontin acted through integrin receptors on microglia to enhance microglial reparative activity, consequently promoting oligodendrogenesis and white matter repair. Increasing Treg cell numbers by delivering IL-2:IL-2 antibody complexes after stroke improved white matter integrity and rescued neurological functions over the long term. These findings reveal Treg cells as a neurorestorative target for stroke recovery.
调节性 T（Treg）细胞对长期组织修复的有益影响的确切机制仍难以捉摸。在这里，我们使用单细胞 RNA 测序和流式细胞术发现，Treg 细胞在小鼠实验性中风后 1 至 5 周浸润大脑。选择性耗尽 Treg 细胞会减少少突胶质细胞生成、白质修复和中风后的功能恢复。转录组分析显示，脑浸润的 Treg 细胞对其他免疫细胞（包括单核细胞谱系细胞）具有强大的免疫调节作用。小胶质细胞耗竭，但 T 细胞淋巴细胞减少症没有，减轻了转移的 Treg 细胞对白质再生的有益作用。在机制上，Treg 细胞衍生的骨桥蛋白通过整合素受体在小胶质细胞上发挥作用，增强小胶质细胞的修复活性，从而促进少突胶质细胞生成和白质修复。中风后通过输送 IL-2：IL-2 抗体复合物增加 Treg 细胞数量可长期改善白质完整性并挽救神经功能。这些发现揭示了 Treg 细胞是中风恢复的神经修复靶标。
