Australian researchers have made a key discovery about the protein MR1 that activates T cells to fight infection, providing new information about the immune system’s defense against bacteria that could help in designing immune-boosting treatments.
MR1, a protein in human cells, plays an important role in bacterial surveillance and is a sort of “antibacterial superhero” that the scientific community has been interested in understanding for quite a while.
During a bacterial infection, MR1 seeks out minute amounts of chemicals made by bacteria as evidence of their presence, and then signals T cells to fight the bacteria.
To better understand how MR1 detects bacterial compounds, a multidisciplinary research team discovered where MR1 first recognizes the bacterial compounds inside the cells as well as the cellular machinery that MR1 relies on.
The research team was co-led by the University of Melbourne’s Hamish McWilliam and Jose Villadangos from the Doherty Institute and the Bio21 Institute, and Jeffrey Mak and David Fairlie from the ARC Center of Excellence in Advanced Molecular Imaging at the Institute for Molecular Bioscience at the University of Queensland. The study was published in the September 21, 2020, issue of the Proceedings of the National Academy of Sciences.
“If a bacteria is nearby, the bacteria release certain chemicals that are signatures of the bacteria, and these chemicals bind to MR1, and that triggers the alarm, and then MR1 goes to the surface of the cell and switches on,” McWilliam told BioWorld Science.
“T cells patrol the body all the time, and they don’t actually sense the bacteria directly. They need to be told through these alarms systems, so that’s what MR1 is. It’s like a mediator between the bacteria and these immune cells, called MAIT cells [mucosal-associated invariant T cells], which are abundant T cells in the body.”
Understanding how MR1 works
Mak and his team at the University of Queensland were able to imitate this bacterial signature by synthesizing a molecule that had a fluorescent tag on it, which ultimately led to the understanding of how MR1 works.
“We could see exactly in the cell where it was binding to MR1 and how that happens, which gave us clues on the part of the cell where MR1 is living and waiting to see if there are bacterial chemicals around,” McWilliam said.
Mak’s team was able to design a “dummy” molecule that imitates the signature made by bacteria, and by attaching a colored fluorescent tag to the molecule, they were able to see it bind to MR1 for the first time under a microscope.
“Unexpectedly, we found this happens inside the cell in an area called the endoplasmic reticulum,” said McWilliam.
“Even though these MR1 cells are abundant in our bodies, very little is known about them, because they were only discovered in the early 2000s, and it was only in 2014 that we had the chemicals to be able to study them, and so this provides an understanding of how this very important and abundant cell fights bacteria,” Mak said.
Being able to tag the molecule with a fluorescent tag will enable drug developers to target MR1, and there might be other molecules that are relevant. Having this information that the target is inside the cell will help guide the strategy for drug developers to get their compounds inside the cell.
“One of the trickiest parts is that the molecule itself is unstable, and so we had to come up with a strategy to mimic a molecule that doesn’t fall apart when we work with it,” Mak said.
The team built the molecule first and identified the ER as the target, and then McWilliam and his team developed the tools, including the CRISPR markers to learn more about MR1.
By identifying the cellular machinery that aids MR1 inside the ER, the team was able to show that MR1 relies on molecular chaperones that help to fold MR1 and keep it in a pre-charged state so in the event of bacterial infection, it can move rapidly to the cell surface where it contacts T cells.
McWilliam said the team used genetic screens using CRISPR to figure out what other proteins MR1 needs to function.
“We also discovered another protein, tapasin, which binds to MR1 and keeps it stable, keeping it from degrading.”
“This is a really powerful arm of the immune system that has the potential to switch on the immune system. Once these MAIT cells are activated, they can easily kickstart inflammation and immune responders through MR1,” McWilliam said.
“If we can understand the molecular details of this system, that will help us to design new drugs to kickstart the immune system or suppress it.
“If you can develop a drug that activates MR1, you can turn on the system, but it was previously not known what part of the cell you needed to target, so this shows what sort of molecules can get inside the ER because that’s where you need to target the drugs.
“We understand how it works in cells, so now we want to see how it targets the whole body,” he said, stressing that the finding underpins many functions in the immune system.
“There are several autoimmune diseases that this system could be active in, such as irritable bowel syndrome, where the body responds to bacteria because the gut lining is damaged.”
The next steps will be to build some more functional molecules using different tags to understand MR1 better.
“We’ve used antibiotics to fight infection but with antibiotic resistance on the rise, developing an immune stimulant could be a possible solution to the resistance problem,” Mak said.
The other application is that instead of just activating the MAIT cells, they can increase the number of them to fight infection (McWilliam, H.E.G. et al. Proc Natl Acad Sci U S A 2020, Advanced publication).