The study provides the first evidence of this mechanism in action and could offer new understanding of the cause of Type 1 diabetes.
Professor Andy Sewell, an expert in human T-cells from Cardiff University’s School of Medicine worked alongside diabetes experts from King’s College London to better understand the role of T-cells in the development of Type 1 diabetes.
The team isolated a T-cell from a patient with Type 1 diabetes to view a unique molecular interaction which results in the killing of insulin-producing cells in the pancreas.
T-cells attacking insulin producing pancreatic beta cells. Cells are stained for insulin (Green) and the killer T-cell marker CD8 (red). The Nuclei are stained blue.
Image: Susan Wong and Maja Wallberg
Some of the funding for this work came from the Biotechnology and Biological Sciences Research Council (BBSRC) in the form of a longer and larger grant (LoLa). LoLas provide internationally-leading research teams with the resources to conduct multidisciplinary research to address major global challenges.
“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,” said Professor Sewell.
“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,” he added.
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 study, funded by BBSRC, 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.
“The results of Dr Sewell’s work provide key novel insights into T1D pathogenesis” said Teodora Staeva, Director of JDRF’s Immune Therapies Program. “JDRF is pleased to support this kind of research that will accelerate the development of biomarkers and preventive therapies for Type 1 diabetes.”
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.
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 1.3M 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 1.3M 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.
Notes to editors
“Structural basis of human b-cell killing by preproinsulin-specific CD8+ T-cells in type 1 diabetes” was published in the journal, Nature Immunology (15/01/12). “A single autoimmune T-cell receptor recognises over a million different peptides” was published in the Journal of Biological Chemistry (06/01/12). Copies of the papers are available on request.
Further information on Professor Sewell’s T-cell research is also available at: www.tcells.org.
Further information on Professor Peakman’s diabetes research is also available at: www.kcl.ac.uk.
About Cardiff University
Cardiff University is recognised in independent government assessments as one of Britain’s leading teaching and research universities and is a member of the Russell Group of the UK’s most research intensive universities. Among its academic staff are two Nobel Laureates, including the winner of the 2007 Nobel Prize for Medicine, University President Professor Sir Martin Evans.
Founded by Royal Charter in 1883, today the University combines impressive modern facilities and a dynamic approach to teaching and research. The University’s breadth of expertise in research and research-led teaching encompasses: the humanities; the natural, physical, health, life and social sciences; engineering and technology; preparation for a wide range of professions; and a longstanding commitment to lifelong learning. Three major new research institutes, visit: www.cardiff.ac.uk/research/index.html for more information, offering radical new approaches to neurosciences and mental health, cancer stem cells and sustainable places were announced by the University in 2010. www.cardiff.ac.uk
About King’s College London
King’s College London is one of the top 30 universities in the world (2011/12 QS World University Rankings), and the fourth oldest in England. A research-led university based in the heart of London, King’s has nearly 23,500 students (of whom more than 9,000 are graduate students) from nearly 140 countries, and some 6,000 employees. King’s is in the second phase of a £1 billion redevelopment programme which is transforming its estate.
King’s has an outstanding reputation for providing world-class teaching and cutting-edge research. In the 2008 Research Assessment Exercise for British universities, 23 departments were ranked in the top quartile of British universities; over half of our academic staff work in departments that are in the top 10 per cent in the UK in their field and can thus be classed as world leading. The College is in the top seven UK universities for research earnings and has an overall annual income of nearly £450 million.
King’s has a particularly distinguished reputation in the humanities, law, the sciences (including a wide range of health areas such as psychiatry, medicine, nursing and dentistry) and social sciences including international affairs. It has played a major role in many of the advances that have shaped modern life, such as the discovery of the structure of DNA and research that led to the development of radio, television, mobile phones and radar. It is the largest centre for the education of healthcare professionals in Europe; no university has more Medical Research Council Centres.
King’s College London and Guy’s and St Thomas’, King’s College Hospital and South London and Maudsley NHS Foundation Trusts are part of King’s Health Partners. King’s Health Partners Academic Health Sciences Centre (AHSC) is a pioneering global collaboration between one of the world’s leading research-led universities and three of London’s most successful NHS Foundation Trusts, including leading teaching hospitals and comprehensive mental health services. For more information, visit: www.kingshealthpartners.org.
About the National Institute for Health Research (NIHR)
The National Institute for Health Research (NIHR) provides the framework through which the research staff and research infrastructure of the NHS in England is positioned, maintained and managed as a national research facility. The NIHR provides the NHS with the support and infrastructure it needs to conduct first-class research funded by the Government and its partners alongside high-quality patient care, education and training. Its aim is to support outstanding individuals (both leaders and collaborators), working in world-class facilities (both NHS and university), conducting leading-edge research focused on the needs of patients. www.nihr.ac.uk.
About Diamond Light Source
Diamond Light Source is funded by the UK Government via the Science and Technology Facilities Council (STFC) and by the Wellcome Trust. For more information about Diamond visit www.diamond.ac.uk.
Diamond generates extremely intense pin-point beams of synchrotron light of exceptional quality ranging from X-rays, ultra-violet and infrared. For example Diamond’s X-rays are around 100Bn times brighter than a standard hospital X-ray machine.
Many of our everyday commodities that we take for granted, from food manufacturing to cosmetics, from revolutionary drugs to surgical tools, from computers to mobile phones, have all been developed or improved using synchrotron light.
JDRF is the world’s leading type 1 diabetes research charity. JDRF exists to fund research to prevent, better treat and ultimately find the cure for type 1 diabetes and its complications. At a global level JDRF volunteers and staff have been responsible for raising over £900 million to support type 1 diabetes research since the charity’s inception.
JDRF in the UK, affiliated to JDRF International (based in the USA), was founded in 1986. It is an independent charity with its own Board of Directors and registered with the Charity Commission of England and Wales and Scotland. www.jdrf.org.uk.
BBSRC invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge, to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond.
Funded by Government, and with an annual budget of around £445M, we support research and training in universities and strategically funded institutes. BBSRC research and the people we fund are helping society to meet major challenges, including food security, green energy and healthier, longer lives. Our investments underpin important UK economic sectors, such as farming, food, industrial biotechnology and pharmaceuticals.
Professor Andy Sewell, School of Medicine, Cardiff University
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