BACKGROUND. Figure 1: Type 1 diabetes results from immune attack on insulin-producing beta-cells in the pancreas

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1 BACKGROUND Diabetes Diabetes is used to describe diseases where a person has high blood sugar. There are three main types of diabetes: Type 1 diabetes results from a failure to produce a hormone called insulin; Type 2 diabetes results from a failure to use insulin properly; and, Gestational diabetes can occur in pregnancy in women that have not had diabetes before. It is estimated that, globally, almost 300 million people (or 5 times the entire population of the UK!) live with diabetes. There is no cure for Type 1 or Type 2 diabetes and these diseases incur a huge social and financial burden. The cost of diabetes It is estimated that the treatment of diabetes, and the complications that arise from it, accounts for over 10% of the National Health Service (NHS) budget in the UK. Medications for the treatment of diabetes account for over 8% of the NHS drugs bill. Type 1 diabetes This form of the disease can be particularly distressing for parents as it often occurs very early in life (although it can be diagnosed at any time). Type 1 diabetes used to be called juvenile diabetes to reflect this early onset. The incidence of type 1 diabetes is increasing in Western Europe by about 5% per year. In 2005 there were 15,000 new cases; it is predicted that by 2020 there will be 24,000 new cases. This rise is particularly steep in under 5- year olds where the disease is predicted to double before Type 1 diabetes results from an autoimmune attack (where the immune system attacks our own body) on cells called beta- cells in an organ called the pancreas. Our pancreatic beta- cells produce the hormone insulin. Insulin controls blood sugar levels. A lack of insulin is rapidly fatal if left untreated. Treatment for type 1 diabetes requires the life- long administration of insulin, usually by injection, and continuous blood sugar monitoring (which can be a difficult task - especially in young children) Figure 1: Type 1 diabetes results from immune attack on insulin-producing beta-cells in the pancreas

2 Type 1 diabetes is an autoimmune disease It is widely acknowledged that type 1 diabetes is the result of an autoimmune attack on insulin- producing beta- cells in the pancreas. The exact mechanism by which these cells are destroyed is not fully understood although there is increasing evidence pointing towards killer T- cells (a type of white blood cell). Killer T- cells are immune cells that are designed to seek and destroy body cells that have become infected by germs such as viruses. It is possible that rogue killer T- cells might attack beta- cells to cause disease in type 1 diabetes. The case for killer T-cells causing type 1 diabetes The idea that killer T- cells cause type 1 diabetes is becoming increasingly compelling but remains unproven. Recent research has shown that type 1 diabetes is genetically linked to genes called HLA class I. The role of HLA class I is to present small pieces of all the protein molecules inside a cell to killer T- cells. It is known that killer T- cells with the capacity to kill beta- cells exist in the blood of patients with type 1 diabetes. It has been shown that these cells infiltrate the pancreatic islets early in disease. Beta- cell specific killer T- cells have proven to be essential for disease transfer in animal models of diabetes. As described below, it has now been shown that killer T- cells isolated from a patient with type 1 diabetes can kill human beta- cells in the laboratory. Figure 2: A microscopic image of a killer T-cell engaging a beta cell. Cells are stained for insulin (in green), for the killer T-cell marker CD8 (in red) and for DNA in blue to show the cellular nucleus. This picture was taken by Maja Wallberg using cells provided by Susan Wong.

3 THE NEW RESEARCH First glimpse of how killer T-cells kill beta-cells Our team at Cardiff University School of Medicine are experts in killer T- cells and have collaborated with a team at King s College London to examine the role of killer T- cells in type I diabetes. In a new study, published this week in the top journal Nature Immunology, we have shown that a killer T- cell that was isolated from a patient with type 1 diabetes can kill human beta- cells. This cell is known to recognise a small piece of the insulin molecule called a peptide that is presented at the beta cell surface by an HLA class I molecule called HLA A2. The team were able to manufacture the insulin- peptide bound to HLA A2 and the molecule on the killer T- cell surface that recognises it called a T- cell receptor in the laboratory. These molecules were then crystallised together and a put in an X- ray beam at Diamond Light Source. The X- rays at Diamond are 100 billion times brighter than standard hospital X- ray machines. The atoms in the molecules in the crystal can scatter these X- rays to produce a scatter pattern. This pattern can then be used to pinpoint where these atoms are and so build a molecular picture of the molecules in the crystal. This has allowed the first ever glimpse of a T- cell receptor from an autoimmune killer T- cell (Figure 3). This structure shows that the interaction between the T- cell receptor and the insulin peptide- HLA complex is abnormal. It is believed that this abnormal binding may allow this killer T- cell to circumvent the safety checks that are designed to cull killer T- cells that attack self. Figure 3

4 How does type 1 diabetes begin? Further recent research from the Cardiff and King s teams and published in the Journal of Biological Chemistry last week (January 6 th 2012) has shown that this insulin- specific T- cell can recognise over a million other peptides in addition to the peptide derived from the insulin molecule. This work provides an interesting potential mechanism for understanding disease pathogenesis and suggests that the autoimmune T- cell could have been raised to fight an infection via one of the many other peptides that the T- cell recognises. This T- cell might then inadvertently attack beta cells once it is put on red alert by the infection. It is known that there are links between the initiation of autoimmunity and recent infections. The structure of the autoimmune TCR published in Nature Immunology provides an interesting potential mechanism by which the disease might be caused. Further work is in progress that will attempt to establish this connection. Figure 4

5 THE IMPLICATIONS AND FUTURE DIRECTIONS The recent work described above and going on in several laboratories around the globe shows that killer T- cells could have a pivotal role in triggering autoimmune diseases like type 1 diabetes in genetically predisposed individuals. The solving of the molecular structure of a killer T- cell receptor in complex with part of the insulin molecular provides a new insight into the potential mechanism by which type 1 disease might be caused. Several new technologies that have been pioneered in Cardiff and elsewhere now allow the detection of killer T- cells in patient blood. The Cardiff and King s team have recently collaborated to show the existence of killer T- cells that bear T- cell receptors that could enable them to kill human beta cells. The existence of these cells in the bloodstream could therefore be an early sign of disease way before the onset of symptoms. Planned studies hope to establish that these cells can be used as such a biomarker for type 1 diabetes. Early diagnosis will allow early treatment before the remaining insulin- producing beta- cells are destroyed. Early treatment is known to result in better patient prognosis. In addition, close monitoring of beta- cell specific killer T- cells might prove to be a valuable readout in forthcoming immunotherapy trials. Figure 5

6 NOTES This piece was written by Professor Andrew Sewell and Dr. Garry Dolton of Cardiff University School of Medicine on January 13 th, 2012 and is aimed at a non- expert audience. We have tried to keep the piece as factually correct as possible. We apologise for any mistakes or omissions. We thank Ania Skowera for helpful suggestions. The recent publications referred to are: Wooldridge, L., J. Ekeruche-Makinde, H.A. van den Berg, A. Skowera, J.J. Miles, M.P. Tan, G. Dolton, M. Clement, S. Llewellyn-Lacey, D.A. Price, M. Peakman and A.K. Sewell (20011) A single autoimmune T-cell receptor recognises over a million different peptides. Journal of Biological Chemistry, 287, (January 6 th, 2012 print edition) Bulek, A.M, D.K. Cole, A. Skowera, G. Dolton, S. Gras, F. Madura, A. Fuller, J.J. Miles, E. Gostick, D.A. Price, J.W. Drijfhout, R.R. Knight, N. Lissin, P.E. Molloy, L. Wooldridge, B.K. Jakobsen, J. Rossjohn, M. Peakman, P.J. Rizkallah and A.K. Sewell (2011) Structural basis of human β-cell killing by preproinsulin-specific CD8+ T-cells in type 1 diabetes. Nature Immunology (published on line January 15 th, 2012) This work was a collaborative effort that involved several teams. In addition to the Cardiff groups headed by Professor Andrew Sewell and Dr. Pierre Rizkallah, Professor Mark Peakman s group at King s College London played a very prominent role. The King s group isolated the T-cell used in these studies and showed that it could kill human beta-cells in the laboratory. For further information on the King s team please see: This work was also supported by help from the laboratory of Cardiff University Honorary Professor Jamie Rossjohn ( html) FUNDING This work was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) UK and the Juvenile Diabetes Research Foundation. Unfortunately, Dr. Dolton s funding ended last year and he is currently unable to continue his Type 1 diabetes work. If you are interested in adopting (or partially adopting) a researcher in this area please get in contact.