Investigating Type I diabetes

“Type 1 diabetes is a result of the body’s own immune system attacking and destroying the cells in the pancreas that manufacture the hormone insulin. Insulin controls blood sugar levels and a lack of insulin is fatal if untreated. The mechanism by which the body attacks its own insulin producing cells in the pancreas is not fully understood. Our findings show how killer T-cells might play an important role in autoimmune diseases like diabetes and we’ve secured the first ever glimpse of the mechanism by which killer T-cells can attack our own body cells to cause disease.”

Professor Andy Sewell, School of Medicine, Cardiff University

Dr Pierre Rizkallah, from Cardiff University, led the crystallography experiments at Diamond. He explains “This 2 year study benefited from regular access to the state-of-the-art crystallography beamlines at Diamond. We were able to collect enough data to a sufficiently high resolution that gave us a handle on structure determination, and then the refinement was straightforward.”

  

Co-author of the study, Professor Mark Peakman from the National Institute for Health Research (NIHR) Biomedical Research Centre at King’s College London and Guy’s and St Thomas’ NHS Foundation Trust said: “This first sight of how killer T-cells make contact with the cells that make insulin is very enlightening, and increases our understanding of how Type 1 diabetes may arise.

 

“This knowledge will be used in the future to help us predict who might get the disease and also to develop new approaches to prevent it. Our aim is to catch the disease early before too many insulin-producing cells have been damaged.”

 

The team now hope that by gaining a better understanding of this process it will put them in a much stronger position to devise new ways to prevent or even halt the disease.

 

The image to the right shows killer T-cells engaging and killing beta cells. The cells are stained for insulin in green, CD8 (a marker of killer T-cells) in red and with a blue nuclear stain to show the cell nucleus (the genetic material). Images courtesy of Susan Wong and Maja Wallberg.

 

The study, funded by the Biotechnology and Biological Sciences Research Council (BBSRC) UK, the Juvenile Diabetes Research Foundation (JDRF) using facilities at Diamond Light Source and published in Nature Immunology, shows that the killer T-cell receptor utilises an abnormal mode of binding in order to recognise cells producing insulin.

 

This unusual binding is thought to allow the T-cell to survive the culling process designed to rid the body of autoreactive T-cells.

 

The structure of the killer T-cell receptor bound to the insulin peptide shows that the interaction is highly focused on just a small part of the molecule (left).

 

In a further study published in the Journal of Biological Chemistry the same Cardiff and King’s team has shown that this focused binding mode allows this T-cell receptor to respond to over 1.3 million other peptides of different molecular shape.

 

This ability to bind peptides with a multitude of different shapes may provide a clue as to how autoimmune diseases are initiated. It is possible that this T-cell was raised to fight an infection via one of the other 1.3 million peptides it can recognise but then inadvertently also recognised insulin once it had been put on ‘red alert’ by this infection.

 

Diabetes describes diseases where a person has high blood sugar. Treatment of diabetes and its complications represents a major health burden and accounts for over 10% of the National Health Service’s annual budget.

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