Engineered T cell therapy for central nervous system injury

Wenqing Gao (), Min Woo Kim, Taitea Dykstra, Siling Du, Pavle Boskovic, Cheryl F. Lichti, Miguel A. Ruiz-Cardozo, Xingxing Gu, Tal Weizman Shapira, Justin Rustenhoven, Camilo Molina, Igor Smirnov, Yifat Merbl, Wilson Z. Ray and Jonathan Kipnis ()
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Wenqing Gao: School of Medicine
Min Woo Kim: School of Medicine
Taitea Dykstra: School of Medicine
Siling Du: School of Medicine
Pavle Boskovic: School of Medicine
Cheryl F. Lichti: School of Medicine
Miguel A. Ruiz-Cardozo: School of Medicine
Xingxing Gu: School of Medicine
Tal Weizman Shapira: The Weizmann Institute of Science
Justin Rustenhoven: School of Medicine
Camilo Molina: School of Medicine
Igor Smirnov: School of Medicine
Yifat Merbl: The Weizmann Institute of Science
Wilson Z. Ray: School of Medicine
Jonathan Kipnis: School of Medicine

Nature, 2024, vol. 634, issue 8034, 693-701

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41586-024-07906-y

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