New research in mice shows that T cells prevent the regeneration of damaged nerve cells due to a reversible, age-related mechanism. Previous studies have shown that aging affects the ability of nerve cells to regenerate after injury, which may affect recovery and lead to long-term disability. However, little is known about the biological mechanism of this decline in regeneration, and there is no treatment to help repair damaged nerve cells.
Now, a new mouse study led by researchers at Imperial College London shows that this may be because T cells block the regeneration signal of nerve cells with age.
The findings, published in the journal Science, also provide positive evidence that these T cells can be inhibited by targeted drugs called monoclonal antibodies to restore and improve nerve cell regeneration.
Sequencing clues
To better understand the mechanism of age-related decline in nerve cell regeneration, the team sequenced RNA in young and old mice before and after sciatic nerve injury. RNA sequencing is a technique used to identify which genes in different types of cells are expressed (turned on) or inhibited (turned off) over time.
The researchers sequenced a specific neural network symmetrical to the dorsal root ganglion and found that the highest number of significantly differently expressed genes appeared in elderly mice after injury. The "opened" gene pattern also seems to be related to adaptive immune response, especially T cells and cytokine / chemical factor signals.
Target T cells
Chemokines are small proteins that stimulate cell migration. The team found that a chemokine called CXCL13, which is specifically induced in neurons of elderly animals, can attract T cells called CD8 + T cells, or cytotoxic T cells. These cells have also been shown to inhibit the regeneration of nerve cells after injury in elderly mice. Importantly, the researchers used humanized monoclonal antibodies against CXCL13 to consume cytotoxic T cells in elderly mice after sciatic nerve injury.
Monoclonal antibodies are laboratory made molecules that act similarly in mice and humans to change the way our immune system interacts with different cells. They are used to treat many different diseases, 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 change the aging dependent regeneration of nerve cells after injury.
Next steps
This study shows that an age-related mechanism enables cytotoxic T cells to prevent the regeneration of damaged nerve cells, and monoclonal antibodies can be used as an effective treatment. Researchers now need to investigate whether the current findings can be replicated in humans.
Senior author Professor Simone di Giovanni commented. "The use of monoclonal antibodies to prevent these T cells from damaging nerves can promote the repair and recovery of a large number of people affected by traumatic nerve injury. This may also have an impact on a range of diseases, such as neuropathy in the context of diabetes, cancer and autoimmune diseases. We still need to test whether these T cells cause damage to human nerve cells and whether monoclonal antibodies can promote repair. We are also To explore whether this mechanism and treatment strategy can promote the repair and recovery after spinal cord injury.
Professor Giovanni added. "T cells that damage nerves in older animals are also T cells that usually protect us from viruses, including covid-19. In older people, these cells penetrate the nervous system and other organs, resulting in tissue damage. This is one of the reasons why older people are more vulnerable to viral infection and tissue damage, including in the nervous system. Therefore, offsetting this problem may protect people from viral infection and neurodegeneration Sexual impact ".