Traumatic injuries to the central nervous system (CNS) afflict millions of individuals worldwide¹, yet an effective treatment remains elusive. Following such injuries, the site is populated by a multitude of peripheral immune cells, including T cells, but a comprehensive understanding of the roles and antigen specificity of these endogenous T cells at the injury site has been lacking. This gap has impeded the development of immune-mediated cellular therapies for CNS injuries. Here, using single-cell RNA sequencing, we demonstrated the clonal expansion of mouse and human spinal cord injury-associated T cells and identified that CD4⁺ T cell clones in mice exhibit antigen specificity towards self-peptides of myelin and neuronal proteins. Leveraging mRNA-based T cell receptor (TCR) reconstitution, a strategy aimed to minimize potential adverse effects from prolonged activation of self-reactive T cells, we generated engineered transiently autoimmune T cells. These cells demonstrated notable neuroprotective efficacy in CNS injury models, in part by modulating myeloid cells via IFNγ. Our findings elucidate mechanistic insight underlying the neuroprotective function of injury-responsive T cells and pave the way for the future development of T cell therapies for CNS injuries.

中枢神经系统 （CNS） 的创伤性损伤折磨着全球数百万人¹，但有效的治疗方法仍然难以捉摸。在此类损伤后，该部位由大量外周免疫细胞（包括 T 细胞）组成，但缺乏对这些内源性 T 细胞在损伤部位的作用和抗原特异性的全面了解。这一差距阻碍了免疫介导的 CNS 损伤细胞疗法的发展。在这里，使用单细胞 RNA 测序，我们证明了小鼠和人脊髓损伤相关 T 细胞的克隆扩增，并发现小鼠中的 CD4 ⁺ T 细胞克隆对髓鞘和神经元蛋白的自身肽表现出抗原特异性。利用基于 mRNA 的 T 细胞受体 （TCR） 重建，一种旨在最大限度地减少自身反应性 T 细胞长时间激活的潜在不利影响的策略，我们生成了工程化的瞬时自身免疫 T 细胞。这些细胞在 CNS 损伤模型中表现出显着的神经保护功效，部分原因是通过 IFNγ 调节髓系细胞。我们的研究结果阐明了损伤反应性 T 细胞神经保护功能背后的机制见解，并为 CNS 损伤 T 细胞疗法的未来发展铺平了道路。