Calling all MAITs: teaming up to solve the intricacies of the immune system

Specialised immune cells, called MAIT cells, receive activation signals from the immune system to fight bacteria. Without the right signals and guidance, they can contribute to cancer and autoimmune diseases.

Little was known about how signals were provided to MAIT cells, until now. Australian-based researchers have zoomed in on the molecular intricacies of the ‘go’ signal to learn how it is initiated and how we can boost it for therapeutic purposes.

MAIT cells sit in common sites of infection, primed to rapidly combat invading bacteria and yeast by recognising the presence of products made along the way when bacteria produce vitamin B.

Humans are not able to produce vitamin B, instead sourcing it from our diet. The presence of the building blocks of vitamin B in the body therefore signify the presence of bacteria and/or yeast as they must be coming from them rather than our own cells.

A protein called MR1 captures molecules that are building blocks for vitamin B2 (riboflavin) or B9 (folic acid), and other small molecules to hold them up as beacons for MAIT cells to detect – MAIT cells would not interact with them otherwise.

If a MAIT cell interacts with MR1 and riboflavin compound, it becomes an activated fighter for the immune system, but if a folic acid compound is captured by MR1 instead, most MAIT cells will not see it and do nothing (as though it were covered in an invisibility cloak).

It was this fine-line between whether or not a MAIT cell can see particular small compounds, thereby driving MAIT cell activation, that the researchers wanted to investigate.

Previous work by a research collaboration spanning the Doherty Institute, Monash University and University of Queensland revealed vitamin B as the trigger for MAIT cell activation.

Building on this foundation, the same research groups aimed to determine the rules that govern this activation process. They developed a suite of riboflavin derivatives to find one that provides the best response, potentially for use in therapy, in a study published today in Nature Immunology.

“Our aim was to learn how much the components of the antigen move around in solution and which ones are critical for sandwiching between the two target proteins to bind then activate the MAIT immune cell,” says Professor David Fairlie, a senior researcher on the study.

Miss Geraldine Ler, Dr Weijun Xu and colleagues in Professor David Fairlie’s research group at the University of Queensland synthesised and characterised a suite of small molecules as chemical variants of the riboflavin-based molecules that activate MAIT cells. Dr Alexandra Corbett and colleagues at the Doherty Institute then tested their ability to bind MR1 and activate MAIT cells. Dr Wael Awad and Professor Jamie Rossjohn at the Monash Biomedicine Discovery Institute zoomed in on the molecular interactions between MAIT cells, MR1 and the vitamin B derivatives.

“When MR1 captures vitamin B derivatives, they are mostly buried so that MAIT cells can only see a minute section that pokes out. It is therefore surprising that such a small part can drive either activation or inhibition, so we wanted to look a little closer,” says Dr Corbett, another senior researcher on the study.

“We investigated three essential properties of each compound: how long they last before breaking down, their ability to coax cells to put more MR1 on their surface so that they can call on more MAIT cells, and how the MAIT cells can see these MR1-‘go’ signals, resulting in their activation. We were able to discover the rules that govern MAIT cell activation, how MAIT cells discriminate between different vitamin B derivatives, and how we can better design potent targets,” she said.

“Using advanced imaging tools, we unearthed the molecular principles underpinning how MR1 captures and presents these small molecules to MAIT receptors triggering the ‘go’ signals,” Dr Awad, first author on the study, said.

“Here, a focused network of nano-connections termed ‘MAIT Interaction Triad’ fine-tunes this process between MR1, metabolite, and MAIT receptor. These discoveries could pave the way for development of novel T cell therapy,” he said.

“This study demonstrates the power of collaboration and the insights we can gain with inter-disciplinary science,” Dr Corbett said.

The more that is understood about MAIT cells and the nuances that boost or prevent their activation, the better they can be manipulated in the context of disease.

Amplifying MAIT cell responses to invading bacteria may help to control infections. In other contexts, however, MAIT cells can be destructive, such as in chronic infections and cancer. Being able to enhance or block them by controlling the visibility of riboflavin compounds and the “go” signals may therefore be highly beneficial for infection, cancer, inflammatory bowel disease, and a range of other diseases.

With this new insight, the teams of Doherty Institute, Monash University and University of Queensland researchers can now design drugs that either activate or block MAIT cells as new immunotherapy targets; potentially for a multitude of diseases.

Read the full paper in Nature Immunology titled The molecular basis underpinning the potency and specificity of MAIT cell antigens.

Nature Immunology cover image 

Original article

Vision Australia Radio interview – Erica on accessibility in the arts

Kenneth Phua recently invited Dr Erica Tandori of Monash University onto his program ‘Seeing Without Eyes’ to discuss accessibility in the arts. Art can be and should be accessible to the total population and not just a select few. If you love the arts, this is an interview highlight from Vision Australia Radio in Perth that you shouldn’t miss.

Original article

Vision Australia Radio interview – Erica on Art & Ophthalmology

Kenneth Phua recently invited Dr Erica Tandori of Monash University onto his program ‘Seeing Without Eyes’ to discuss accessibility in the arts. Kenneth enjoyed the discussion so much he invited Erica back once again to hear more about her career. Erica discusses her vision loss, her experience of dealing with the medical industry and finding a way forward with her passion for visual art.

Original article

Discovery of new T-cell raises prospect of ‘universal’ cancer therapy

Researchers at Cardiff University have discovered a new type of killer T-cell that offers hope of a “one-size-fits-all” cancer therapy.

T-cell therapies for cancer – where immune cells are removed, modified and returned to the patient’s blood to seek and destroy cancer cells – are the latest paradigm in cancer treatments.

The most widely-used therapy, known as CAR-T, is personalised to each patient but targets only a few types of cancers and has not been successful for solid tumours, which make up the vast majority of cancers.

Cardiff researchers have now discovered T-cells equipped with a new type of T-cell receptor (TCR) which recognises and kills most human cancer types, while ignoring healthy cells.

This TCR recognises a molecule present on the surface of a wide range of cancer cells as well as in many of the body’s normal cells but, remarkably, is able to distinguish between healthy cells and cancerous ones, killing only the latter.

The researchers said this meant it offered “exciting opportunities for pan-cancer, pan-population” immunotherapies not previously thought possible.

How does this new TCR work?

Conventional T-cells scan the surface of other cells to find anomalies and eliminate cancerous cells – which express abnormal proteins – but ignore cells that contain only “normal” proteins.

The scanning system recognises small parts of cellular proteins that are bound to cell-surface molecules called human leukocyte antigen (HLA), allowing killer T-cells to see what’s occurring inside cells by scanning their surface.

HLA varies widely between individuals, which has previously prevented scientists from creating a single T-cell-based treatment that targets most cancers in all people.

But the Cardiff study, published today in Nature Immunology, describes a unique TCR that can recognise many types of cancer via a single HLA-like molecule called MR1.

Unlike HLA, MR1 does not vary in the human population – meaning it is a hugely attractive new target for immunotherapies.

See original article here

Image: T-cells attacking cancer

 

Our recent coeliac disease research featured in the Age

Coeliac disease linked to bacteria exposure

The Age article by Liam Mannix. Original article

Exposure to bacteria that mimics gluten can confuse the immune system and trigger coeliac disease, Melbourne scientists have shown for the first time.

The results raise the possibility of using probiotics or developing a vaccine to prevent the disease, which affects nearly 400,000 Australians.

Some of the suspect bacteria lives naturally in our guts – which might explain why people with coeliac disease can still suffer even after eliminating gluten from their diet.

“This is the first time we have shown a potential mechanism for why the microbiome may be involved in the initiation of this disease,” says Hugh Reid, the Monash University researcher who led the multi-institute study.

The study also has big-picture implications. If bacteria have proteins that mimic gluten, they probably have proteins that mimic lots of things people are allergic to. Could it be that bacteria and viruses trigger many common autoimmune conditions?

Molecular mimics

Coeliac disease occurs when the body’s immune system begins reacting to gluten, a protein found in wheat, rye and barley.

When someone with the disease eats gluten, their immune system misidentifies it as a foreign invader. It mounts a huge immune response in the gut, trying to “kill” the gluten – which can lead to bloating, diarrhoea and intestinal damage.

About 50 per cent of people carry the genes that make them susceptible to coeliac disease, but these people are not born allergic to gluten. Only one in 70 with the genes ever develops it.

It seems they come across some sort of trigger as children, activating the condition before their immune system has fully matured. Scientists have long suspected mimics are to blame.

A small number of viruses and bacteria produce protein fragments that look almost identical to parts of gluten – “molecular mimics”, scientists call them.

The team used molecular databases to assemble a set of protein fragments produced by bacteria that looked near-identical to gluten. They ended up with about 20, many produced by species that live naturally – and harmlessly – within our gut.

Then researchers at the Walter and Eliza Hall Institute took blood from people with coeliac disease, and exposed the immune cells to the gluten mimics the team had found.

Immediately, the immune cells went on the attack – just like if they had spotted a molecule of gluten. “It’s a case of mistaken identity,” says Dr Reid.

To confirm the results, they used the Synchrotron, a 200-metre-long tube buried under the Melbourne suburb of Clayton that shoots out light 1 million times brighter than the sun, to take a high-resolution molecular photograph of the bacterial protein fragments as they reacted with immune system molecules.

The images looked identical to the way the gluten fragments reacted with the same molecules. “That nailed it,” says Dr Reid.

The smoking gun

The team’s paper, published in Nature Structural and Molecular Biology, is the smoking gun for the molecular mimic theory, but there are lots of questions still to be answered.

The big one: if these mimic-bacteria live in many people’s guts, why doesn’t everyone with susceptible genes get coeliac disease?

The answer may have to do with the number of bacteria, Dr Reid says.

The immune system might happily tolerate a small number of mimic bacteria living in our guts. But if there are too many, it might go on the attack.

It might then remember that attack – our immune systems are designed to remember viruses and bacteria they come across – and mount an offensive whenever it sees a similar molecule. Like gluten.

That would explain why studies have shown children who develop coeliac disease tend to have abnormal microbiomes.

Using antibiotics, which kill off healthy gut bugs and open space for other ones to thrive, is also linked to developing coeliac disease.

Perhaps this allows the number of mimic bacteria to grow high enough to trigger the disease?

“There are a lot of questions that are not answered by this,” says Dr Reid. “But we have paved the way for developing strategies for preventing this disease.

“We could vaccinate people against this particular bacteria, potentially, or use probiotics.”