Microbial signatures provide key to immunosurveillance

The discovery of the biochemistry involved in initiating the immune system’s first line of defence against foreign invaders in mucosal tissues is expected to lead to new ways of diagnosing and treating inflammatory bowel disease, peptic ulcers and even tuberculosis.

The patented work has revealed how immune cells, known as mucosal-associated invariant T cells (MAIT cells), initiate the immune system’s action against foreign invaders when they are exposed to riboflavin (vitamin B2), which is made by bacteria and fungi.

“Our intestines, lungs and mouths are lined with mysterious immune cells that make up to 10% of the T cells in our immune system. Last year we showed that these cells act as sentinels against invading bacteria and fungi. Now we’ve identified the precise biochemical key that wakes up these sentries and sends them into action,” said one of the lead researchers, Professor James McCluskey, University of Melbourne Deputy Vice-Chancellor (Research).

The researchers showed that MAIT-cell activation requires key genes encoding enzymes that form 5-amino-6-d-ribitylaminouracil (5-A-RU), an early intermediate in bacterial riboflavin synthesis.

They then found that the riboflavin precursors are presented to the MAIT cells not by binding major histocompatibility complex-related protein or by activating MAIT cells directly, but by forming MAIT-activating antigens via non-enzymatic reactions with small molecules derived from other metabolic pathways.

The discovery is the result of national and international collaboration between the universities of Melbourne, Monash, Queensland and Cork.

“MAIT cells are a discovery so recent that they have not even made it into the textbooks,” Professor McCluskey said, adding that the research builds on work conducted last year that was acknowledged with an Australian Museum Eureka Prize in 2013.

“Most doctors know nothing about them. Yet they constitute about one cell in 10 of the body’s T cells and half of all the T cells in the liver.

“This is an excellent example of how our collaborative research in Australia can bring groups with expertise in different areas together to make significant advances,” Professor McCluskey said.

Dr Alexandra Corbett, a lead author on the study from the University of Melbourne, said the team had unlocked a secret that will enable further investigation in the role that MAIT cells play in health and disease.

Professor Jamie Rossjohn, one of the senior authors and NHMRC Australia Fellow of Monash University, also noted the close collaborations that resulted in these findings.

“To get from the first observation to today’s discovery required not just smart people but access to Melbourne’s Bio21 Institute platforms, dozens of visits to the Australian Synchrotron and a global research network including our Irish colleagues who provided access to mutant bacterial strains.”

The work was recently published in Nature