Engineered T cell therapy for central nervous system injury

• Published in: Nature (London) 2024-10, Vol.634 (8034), p.693-701
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 631/250/371; 631/378/371; 64; 64/60; 82/58; Animals; Antigens; Autoantigens; Autoimmunity; CD4 antigen; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; Cell activation; Cell culture; Cell Engineering - methods; Cell therapy; Cell- and Tissue-Based Therapy - methods; Central nervous system; Central Nervous System - immunology; Central Nervous System - injuries; Clone Cells; Cloning; Cytotoxicity; Disease Models, Animal; Effectiveness; Female; Gene sequencing; Humanities and Social Sciences; Humans; Immune system; Injuries; Interferon-gamma - immunology; Interferon-gamma - metabolism; Lymphocytes; Lymphocytes T; Male; Mice; Mice, Inbred C57BL; mRNA; multidisciplinary; Myelin; Myelin Sheath - immunology; Myelin Sheath - metabolism; Myeloid cells; Myeloid Cells - immunology; Nervous system; Neuroprotection; Optic nerve; Peptides; Proteins; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; Science; Science (multidisciplinary); Single-Cell Analysis; Spinal cord injuries; Spinal Cord Injuries - immunology; Spinal Cord Injuries - therapy; T cell receptors; T-Lymphocytes - immunology; T-Lymphocytes - transplantation; Transgenic animals; γ-Interferon
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-024-07906-y

Traumatic injuries to the central nervous system (CNS) afflict millions of individuals worldwide 1 , 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. This study presents a new T cell therapy targeting spinal cord injury, providing a potential new approach for injured CNS.