Nerve tissue is not capable of significant regeneration in mammals, but the existing limited capacity for regrowth is further diminished with age. Researchers here show that one of the major classes of T cell of the adaptive immune system causes a meaningful fraction of this diminished regenerative capacity. Prevent these T cells from engaging with injured tissue and nerve regeneration is improved as a result, at least in mice. The approach used here may form the basis for an approach to greater recovery following injury in older people, and possibly even improved maintenance of nervous system tissue in later life.
Axonal regeneration and neurological functional recovery are extremely limited in the elderly. Consequently, injuries to the nervous system are typically followed by severe and long-term disability. We hypothesized that injuries to the aged nervous system would be followed by unique molecular and cellular modifications that would contribute to aging-dependent regenerative decline. To this end, molecular and cellular signatures associated with aging and injury to the nervous system were systematically investigated by performing RNA sequencing from dorsal root ganglia (DRG) in a well-established model of sciatic nerve injury in young versus aged mice.
Initial analysis of RNA sequencing data identified that aging was mainly associated with a marked increase in T cell activation and signaling in DRG after injury. Subsequent experiments demonstrated that aging was associated with increased inflammatory cytokines in DRG both preceding and following sciatic nerve injury. Specifically, we found that lymphotoxin β was required for the phosphorylation of NF-κB that drives the expression of the chemokine CXCL13 in DRG sensory neurons. CXCL13 attracted CD8+ T cells that expressed the CXCL13 receptor CXCR5 in proximity to neurons that act as antigen-presenting cells by overexpressing major histocompatibility complex class I (MHC I) after injury. The engagement of CXCR5+CD8+ T cells with MHC I-expressing sensory neurons activated caspase 3, which leads to regenerative failure.
Neutralization of CXCL13 with monoclonal antibodies reduced the recruitment of CXCR5+CD8+ T cells to the DRG and restored the regenerative ability of sciatic sensory axons in aged mice to levels comparable to those found in young animals. CXCL13 antagonism also significantly promoted skin reinnervation and neurological recovery of sensory function.