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, Jonathan Kipnis

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)693-701
Number of pages9
JournalNature
Volume634
Issue number8034
DOIs
StatePublished Online - 4 Sep 2024

All Science Journal Classification (ASJC) codes

  • General

Cite this