For almost a decade, scientists have wondered why blood cells that are crucial to the body’s defences against infection also produce a molecule that is better known for its role in conducting signals within the brain.
Now, researchers at the Princess Margaret Cancer Centre in Toronto think they’ve found the answer: The molecule, called acetylcholine, is used by immune cells to trigger a chemical chain reaction that loosens blood vessels, opening a doorway into infected tissues.
While the new result stems from work with mice, it points to a surprising range of possible applications, from better success rates for cancer immune therapies to more effective flu vaccines. It also speaks to an emerging connection between the nervous system and the immune system that is increasingly attracting attention.
“It tells us why [acetylcholine] may be involved in so many important chronic diseases,” said Tak Mak, a renowned expert in genetics and immunology and a Canadian Medical Hall of Fame inductee whose lab led the research.
Dr. Mak is best known for discoveries in the 1980s that relate to how T cells – the cells that co-ordinate the body’s response to infection – recognize foreign invaders. The work paved the way for discoveries by other scientists, such as how cancer thwarts the immune system by switching T cells off and how that action, in turn, can be prevented with immunotherapy drugs, the subject of last year’s Nobel Prize in Medicine.
More recently, Dr. Mak’s work has included a scientific partnership with Kevin Tracey, a neurosurgeon at the Feinstein Institute for Medical Research in Manhasset, N.Y. Together with several collaborators, the two scientists have probed the apparent link between T cells and the nervous system.
Evidence of that link dates back to 1849, when Rudolf Wagner, a German physician, realized that stimulating the vagus nerve – one of the cranial nerves connecting the brain to the body – of a dog could produce a response in the spleen, the organ that acts as a reservoir for immune cells, among other functions. Studies have also shown that patients with spinal-cord injuries resulting in paralysis have great susceptibility to infection.
In 2011, Dr. Tracey and Dr. Mak were senior authors on a study that showed that some T cells in the spleen produce acetylcholine in response to neural signals. Starting in 2013, Dr. Mak and his team at Princess Margaret, part of Toronto’s University Health Network, set about trying to understand why. Maureen Cox, a postdoctoral researcher in Dr. Mak’s lab, took on the project.
Working on a hunch that the acetylcholine had something to do with T cells’ role in immunity, she first observed that, in ordinary lab mice, the number of T cells making the chemical rose dramatically during an infection. She also found that the blood vessels in those mice expanded. This made sense because acetylcholine is a vasodilator – a chemical that relaxes the walls of blood vessels.
“What we started thinking was that maybe this is how immune cells are able to migrate into tissues,” Dr. Cox said.
T cells normally roll along in the direction of blood flow until they come across signs of infection, which cause them to adhere to the side of a blood vessel and eventually work their way into the infected tissue. When blood vessels expand, blood flow is slower, which should make it easier for the T cells to stick and get to where they are needed.
To test the idea, Dr. Cox deployed a powerful array of genetic tricks to engineer mice that lacked the ability to produce acetylcholine – but only in their T cells, since no mammal can survive for long without generating the molecule as part of its regular brain function.
When she subjected her engineered mice to a virus, their blood vessels remained unchanged, hindering their ability to fight the infection. The results, published on Friday in the journal Science, suggest that controlling blood flow near infected areas is an important aspect of the body’s immune response to chronic infections, where viruses become established in tissues.
John Bienenstock, a professor and expert in neuroimmunology at McMaster University in Hamilton, who was not involved in the study, said the work “offers insight we’ve not had before” on the role of acetylcholine in immune response. He cautioned that more work would be needed to show that the same process is at play in the human immune system and to clarify what role the nervous system might play in triggering or inhibiting acetylcholine production in response to infection.
Dr. Mak said the results suggest that one reason cancer immune therapies sometimes fail could be connected to how well T cells can penetrate into tissues where tumors are growing.
Dr. Cox, who is leaving Toronto for an appointment in the United States this year, added that she hopes to continue the research to see if she can use it better optimize vaccines.
The Globe and Mail, February 12, 2019