Previous research has shown that ageing impacts the ability of nerve cells to regenerate following an injury, which can impact recovery and lead to long-term disability. However, the biological mechanisms underlying this regenerative decline are poorly understood and there are no treatments available to help repair damaged nerve cells.
Now, a new study in mice led by researchers at Imperial College London has revealed that this may be due to T cells blocking regenerative signals in nerve cells with age.
The findings, published in Science, also provide positive evidence that these T cells can be repressed using targeted drugs called monoclonal antibodies to restore and improve nerve cell regeneration.
To better understand the mechanisms underlying ageing-related regenerative decline in nerve cells, the study team performed RNA sequencing on young and old mice preceding and following a sciatic nerve injury.
RNA sequencing is a technique used to identify which genes are being expressed (switched on) or suppressed (switched off) over time in different types of cells.
Researchers sequenced a specific network of nerve cells called dorsal root ganglia and found the highest number of significantly differentially expressed genes occurred in older mice following injury. The pattern of genes being ‘switched on’ also appeared to be associated with adaptive immune responses, especially T cell and cytokine/chemokine signalling.
Targeting T cells
Chemokines are small proteins that stimulate the migration of cells.
The team discovered that a chemokine known as CXCL13, which is specifically induced in the neurons of aged animals, can attract a type of T cell called CD8+ T cells, or cytotoxic T cells. These in turn were shown to repress nerve cell regeneration after injury in older mice. Importantly, researchers used humanised monoclonal antibodies against CXCL13 to deplete cytotoxic T cells in old mice after a sciatic nerve injury.
Monoclonal antibodies are lab-made molecules which act similarly in mice and humans to change the way our immune system interacts with different cells. They are used to treat many different conditions, including cancer.
By blocking these cytotoxic T cells, the team found that nerve regeneration was significantly improved. The team also observed that other immune cells – CD4 T cells and B cells – did not alter ageing-dependent regenerative decline in nerve cells after injury.
“The use of monoclonal antibodies to prevent these T cells from damaging nerves could promote repair and recovery in individuals affected by traumatic nerve injuries.” Professor Simone Di Giovanni
The study indicates that an ageing-related mechanism enables cytotoxic T cells to prevent damaged nerve cells from regenerating and that monoclonal antibodies could be used as an effective treatment.
Researchers now need to investigate whether the current study’s findings can be replicated in humans.
Senior author Professor Simone Di Giovanni comments: “The use of monoclonal antibodies to prevent these T cells from damaging nerves could promote repair and recovery in a very large population of individuals affected by traumatic nerve injuries. This also has possible implications in a range of conditions such as neuropathies in the context of diabetes, cancer, and autoimmune disorders.”
“We still need to test whether these T cells cause damage to nerve cells in humans and whether monoclonal antibodies can promote repair. We are also exploring whether this mechanism and treatment strategy can promote repair and recovery after spinal cord injuries.”
Professor Di Giovanni adds: “The same T cells that cause damage to the nerves in the aged animals are the ones that typically defend us from viruses including COVID-19.
“In the elderly, these cells leak into the nervous systems and other organs and, as a result, cause tissue damage instead of protecting against viruses. This is one of the reasons why old people are more susceptible to viral infections and to tissue damage, including in the nervous system.
“Counteracting this problem may therefore protect from both viral infections and neurodegeneration.”
‘Reversible CD8 T cell–neuron cross-talk causes ageing-dependent neuronal regenerative decline’ by Luming Zhou, Guiping Kong et al. is published in Science
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