双阴性T细胞在脊髓损伤后通过调控星形胶质细胞反应性增殖发挥神经修复作用的机制研究

脊髓损伤（SCI）是一种严重致残性疾病，损伤后的神经免疫调节对阻止继发性损伤十分关键。双阴性T细胞（DNT细胞）在免疫相关疾病中通过其免疫抑制功能发挥保护作用，但DNT细胞能否通过调节SCI后的免疫反应发挥神经修复作用仍不清楚。我们前期研究表明DNT细胞干预有利于运动功能恢复，显著降低损伤区域高增殖能力的星形胶质细胞比例。据此我们假设，DNT细胞抑制外周和损伤部位的免疫反应，其作用机制可能包括通过颗粒酶/穿孔素途径（Prf1）直接杀伤和/或通过分泌细胞因子间接抑制具有神经毒性反应性星形胶质细胞，进一步抑制胶质瘢痕的形成，最终发挥神经修复作用。我们将通过小鼠SCI打击模型对DNT细胞干预效果进行验证；并利用GFAP-GFP转基因小鼠以及Prf1基因敲除小鼠深入探讨DNT细胞对反应性星形胶质细胞的调节机制。此研究将为SCI的免疫细胞治疗提供支撑，具有潜在的临床应用价值。

Spinal cord injury (SCI) is a serious debilitating disease. The neuroimmune regulation after SCI is crucial in preventing secondary injury. Studies have shown that double-negative T cells (DNT cells) play a positive role in immune-related diseases through their immunosuppressive function. However, whether DNT cells could have a neurorepairing effect by regulating the immune response after spinal cord injury is still unclear. In the previous study, we found that DNT intervention significantly improved the motor function after spinal cord injury. Further studies showed that DNT intervention significantly reduced the proportion of high proliferative astrocytes at the injury site. Therefore, we hypothesize that DNT cells could suppress the immune responses on the periphery and the injury site, and its mechanism may include directly killing the neurotoxic reactive astroglial cells through the perforin/granzyme pathway (Prf1) and/or indirectly suppressing the neurotoxic response of reactive astrocytes and the formation of glial scars through cytokine secretion, which subsequently play a neuroprotective role. We will verify the effect of DNT intervention in traumatic SCI mice, and further explore the regulatory mechanism of DNT cells on reactive astrocytes by Prf1 knockout mice and GFAP-GFP transgenic mice. This study will provide data support for immune cell therapy of spinal cord injury and has the potential for clinical application.