Programmed death protein 1 is essential for maintaining the anti-inflammatory function of infiltrating regulatory T cells in a murine spinal cord injury model
Programmed death protein 1 is essential for maintaining the anti-inflammatory function of infiltrating regulatory T cells in a murine spinal cord injury model
复制标题
程序性死亡蛋白 1 对于维持小鼠脊髓损伤模型中浸润调节性 T 细胞的抗炎功能至关重要。
DOI：
10.1016/j.jneuroim.2021.577546
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发表时间：
2021-03-18
影响因子：
3.3
通讯作者：
Lin, Wenping
中科院分区：
文献类型：
--
作者：
He, Xu;Lin, Shuhui;Lin, Wenping
过度的神经炎症会加重脊髓损伤（SCI）后的神经元损伤。胸腺调节性T细胞（TCFs）、巨噬细胞和小胶质细胞在脊髓损伤后神经炎症过程中发挥重要作用。然而，这些细胞在受损脊髓中被调节的机制仍不清楚。在目前的研究中，我们应用了一种小鼠SCI模型，以证明程序性死亡蛋白1（PD-1）在浸润性T细胞中的上调和程序性死亡配体1（PD-L1）在SCI后巨噬细胞/小胶质细胞上的显著表达。此外，通过使用可诱导的shRNA慢病毒系统，我们表明Treg特异性PD-1敲低损害浸润性TREM的抗炎功能。PD-1对于在促炎性巨噬细胞/小胶质细胞的影响下维持Treg身份和功能至关重要，并且PD-1缺陷型Treg抑制促炎性巨噬细胞/小胶质细胞的能力较低。此外，在使用T和B细胞缺陷型Rag（1-/-）小鼠的鼠SCI模型中，Treg特异性PD-1敲低损害体内Treg介导的神经保护，如通过扩大的损伤面积所证明的。综上所述，我们的研究表明，PD-1在SCI亚急性期的浸润性TGFAP中上调，对于TGFAP维持Foxp 3表达和抗炎活性以抵消促炎巨噬细胞和小胶质细胞的作用至关重要。靶向Treg PD-1的新疗法可能有益于SCI治疗。
Excessive neuroinflammation exacerbates neuronal impairment after spinal cord injury (SCI). Thymic regulatory T cells (Tregs), macrophages, and microglia play significant roles in the process of post-SCI neuroinflammation. However, the mechanisms by which these cells were modulated in the injured spinal cord remain unclear. In the current research, we applied a murine SCI model to demonstrate the upregulation of programmed death protein 1(PD-1) in infiltrating Tregs and significant expression of programmed death-ligand 1 (PD-L1) on post-SCI macrophages/microglia. Furthermore, through using an inducible shRNA lentivirus system, we showed that Treg-specific PD-1 knockdown impairs the anti-inflammatory function of infiltrating Tregs. PD-1 is crucial for the maintenance of Treg identity and function under the influence of pro-inflammatory macrophages/microglia, and PD-1-deficient Tregs are less competent to inhibit pro-inflammatory macrophages/microglia. Besides, in a murine SCI model using T-and-B-cell-deficient Rag(1-/-) mice, Treg-specific PD-1 knockdown impairs Treg-mediated neuroprotection in vivo, as evidenced by enlarged lesion area. Taken together, our study revealed that PD-1, which is upregulated on infiltrating Tregs in the subacute phase of SCI, is essential for Tregs to maintain Foxp3 expression and anti-inflammatory activity to counteract the effect of pro-inflammatory macrophages and microglia. Novel therapies targeting Treg PD-1 might benefit SCI treatment.