Engineered T cell therapy for central nervous system injury

• 成果类型: Article
• 署名作者: Gao, Wenqing; Kim, Min Woo; Dykstra, Taitea; Du, Siling; Boskovic, Pavle; Lichti, Cheryl F.; Ruiz-Cardozo, Miguel A.; Gu, Xingxing; Weizman Shapira, Tal; Rustenhoven, Justin; Molina, Camilo; Smirnov, Igor; Merbl, Yifat; Ray, Wilson Z.; Kipnis, Jonathan
• 署名单位: Washington University (WUSTL); Washington University (WUSTL); Washington University (WUSTL); Washington University (WUSTL); Washington University (WUSTL); Saint Louis University; Washington University (WUSTL); Weizmann Institute of Science
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6809
• DOI: 10.1038/s41586-024-07906-y
• 发表日期: 2024-10-17
• 关键词: single-cell; microglia; oligodendrogenesis; tolerance; RECOVERY; package

摘要

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 IFN gamma. 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. This study presents a new T cell therapy targeting spinal cord injury, providing a potential new approach for injured CNS.