TY - JOUR
T1 - Engineered T cell therapy for central nervous system injury
AU - Gao, Wenqing
AU - Kim, Min Woo
AU - Dykstra, Taitea
AU - Du, Siling
AU - Boskovic, Pavle
AU - Lichti, Cheryl F.
AU - Ruiz-Cardozo, Miguel A.
AU - Gu, Xingxing
AU - Weizman Shapira, Tal
AU - Rustenhoven, Justin
AU - Molina, Camilo
AU - Smirnov, Igor
AU - Merbl, Yifat
AU - Ray, Wilson Z.
AU - Kipnis, Jonathan
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2024.
PY - 2024/10/17
Y1 - 2024/10/17
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85203185038&partnerID=8YFLogxK
U2 - 10.1038/s41586-024-07906-y
DO - 10.1038/s41586-024-07906-y
M3 - Article
C2 - 39232158
AN - SCOPUS:85203185038
SN - 0028-0836
VL - 634
SP - 693
EP - 701
JO - Nature
JF - Nature
IS - 8034
ER -