Reversible CD8 T cell-neuron cross-talk causes aging-dependent neuronal regenerative decline

Aging is associated with increased prevalence of axonal injuries characterized by poor regeneration and disability. However, the underlying mechanisms remain unclear. In our experiments, RNA sequencing of sciatic dorsal root ganglia (DRG) revealed significant aging-dependent enrichment in T cell sig...

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Published in:Science (American Association for the Advancement of Science) 2022-05, Vol.376 (6594), p.eabd5926-eabd5926
Main Authors: Zhou, Luming, Kong, Guiping, Palmisano, Ilaria, Cencioni, Maria Teresa, Danzi, Matt, De Virgiliis, Francesco, Chadwick, Jessica S, Crawford, Greg, Yu, Zicheng, De Winter, Fred, Lemmon, Vance, Bixby, John, Puttagunta, Radhika, Verhaagen, Joost, Pospori, Constandina, Lo Celso, Cristina, Strid, Jessica, Botto, Marina, Di Giovanni, Simone
Format: Article
Language:English
Subjects:
Adoptive transfer
Aging
Aging - metabolism
Anatomy
Animals
Antigen-presenting cells
Antigens
Axons
Axons - physiology
Back injuries
Caspase-3
CD8 antigen
CD8-Positive T-Lymphocytes - metabolism
Cell activation
Chemokines
Crosstalk
CXCL13 protein
CXCR5 protein
Cytokines
Dorsal root ganglia
Failure
Ganglia
Ganglia, Spinal - metabolism
Gene sequencing
Geriatrics
Homeostasis
Inflammation
Injuries
Injury prevention
Lymphocytes
Lymphocytes T
Lymphotoxin
Major histocompatibility complex
Metabolism
Mice
Molecular modelling
Monoclonal antibodies
Nerve Regeneration
Nerves
Nervous system
Neurons
Neurons - metabolism
Neutralization
NF-κB protein
Older people
Phosphorylation
Recovery
Recovery of function
Recruitment
Regeneration
Reinnervation
Repair
Sciatic Nerve - injuries
Sciatic Nerve - physiology
Sensory neurons
Signaling
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Summary:Aging is associated with increased prevalence of axonal injuries characterized by poor regeneration and disability. However, the underlying mechanisms remain unclear. In our experiments, RNA sequencing of sciatic dorsal root ganglia (DRG) revealed significant aging-dependent enrichment in T cell signaling both before and after sciatic nerve injury (SNI) in mice. Lymphotoxin activated the transcription factor NF-κB, which induced expression of the chemokine CXCL13 by neurons. This in turn recruited CXCR5 CD8 T cells to injured DRG neurons overexpressing major histocompatibility complex class I. CD8 T cells repressed the axonal regeneration of DRG neurons via caspase 3 activation. CXCL13 neutralization prevented CXCR5 CD8 T cell recruitment to the DRG and reversed aging-dependent regenerative decline, thereby promoting neurological recovery after SNI. Thus, axonal regeneration can be facilitated by antagonizing cross-talk between immune cells and neurons.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.abd5926