Written by Lauren Robertson, Science Writer.
In a paper published in the journal Glia, researchers have uncovered a new function of Schwann cells (SCs), related to their ability to shut down the immune response during nerve repair and prevent excessive tissue damage.
Though previous studies have suggested SCs interact with immune cells during the inflammatory process, it was not known how exactly this occurred or whether they were able to directly regulate the adaptive immune response after nerve injury.
Phagocytic Schwann cells
SCs are the major glial cell type in the peripheral nervous system. They help form the myelin sheath that protects nerves from damage. In recent years, there has been increasing evidence that SCs play a role in actively repairing nerves – particularly through a process known as “adaptive cellular reprogramming.” During this process, cells re-enter the cell cycle and perform specialised functions, such as recruiting immune cells or remodelling the extracellular matrix. There’s also been evidence that this adaptive immune state plays a role in other neuropathies and in tumour development.
To get a better idea of the role SCs play in nerve regeneration, a team of researchers, led by Sabine Taschner-Mandl, set out to investigate the immunoregulatory features of these cells in nerve injury. First, they analysed the transcriptome, secretome, and cell surface proteins of human repair-related SCs, looking for relevant markers or pathways related to innate and adaptive immunity. They then carried out phagocytosis assays and monitored T-cell subset activation.
To their surprise, they found that SCs can become phagocytic and take up large amounts of material from their environment – meaning they are able to express MHC-I and MHC-II molecules on their surface. Importantly, by expressing these molecules, SCs can influence T cell activation.
As well as their antigen-presenting capabilities, the team also found that SCs were able to express co-regulatory proteins and release a hoard of chemoattractants, matrix remodelling proteins, and both pro- and anti-inflammatory cytokines. If that wasn’t enough, they can also upregulate the T-cell inhibiting PD-L1 molecule in response to IFNγ (a pro-inflammatory mediator).
“This is essential because inflammation releases free radicals against which nerve fibers cannot protect themselves. Therefore, the inflammation must be cleared quickly, which is precisely what Schwann cells do,” explains Taschner-Mandl. Overall, this suggests a new role for SCs as negative regulators of T-cell immunity during nerve regeneration – as non-professional APCs that modulate the inflammatory response in injured nerves. But the value of this study could go one step further – there’s the potential for it to be used in future oncology research.
A potential role in cancer
The “repair” mode that is activated in SCs cells during nerve injury is also found in benign infantile nerve tumours. This ultimately causes tumour cells to mature and reach a stage where they lose their aggressive tendencies and no longer divide unchecked.
“Based on the current results, we now suspect that the immune cell functions of Schwann cells also become effective in childhood nerve tumours,” says Taschner-Mandl. “This is because in cancer, there is always a kind of inflammation bubbling away that never comes to a halt. In benign nerve tumours – ganglioneuromas – the accompanying chronic inflammation could be stopped by Schwann cells similar to nerve healing, because unlike malignancies, benign nerve tumours have many Schwann cells in their microenvironment.”
The team believes that while SCs initially fuel the inflammatory response by releasing interferon-gamma, they can later up-regulate PD-L1 and actually shut inflammation down. “First activate, then shut down – that’s the normal process of an inflammatory response. If this were also the case in cancer, then it could curb cancer growth,” comments Sabine Taschner-Mandl. The next step is to look at exactly how these results could be useful for the development of future cancer therapies.