T cells and Type I Diabetes:
Are IL-18 receptor-bearing CD8 T cells pathogenic in human Type 1 diabetes?
A subset of CD8 T cells have been identified as a potentially harmful population of cells that may contribute to the onset of type I diabetes. Dr. Sarvetnick’s group is targeting this population as a potential marker for diabetes as well as possible focus for therapy. They have shown that the expression of the IL-18 receptor on this particular population of CD8 T cells is significantly expanded in new-onset diabetics. This is a novel discovery by the group. Historically, increased serum levels of IL-18 has been shown to play an important role in many inflammatory diseases of the bowel, heart, joints, and lungs and has even been shown to be a risk factor for type I diabetes.
Dr. Sarvetnick has also shown these cells to be present in a mouse model of diabetes, known as NOD (Non-Obese Diabetic) mice whose disease mimics the spontaneous onset of diabetes in humans. In particular the IL-18R+ cells actually migrate to the islets of the pancreas (see picture below). The group is working to further define this population and depict their developmental patterns in the NOD mouse model. They do know that when IL-18 or IL18R is removed from the NOD mouse (ie. IL-18 or IL-18 R knockout) they see complete protection from development of diabetes. In addition, when mice are given the antagonist of IL-18, IL-18 binding protein, they saw protective effects when they experimentally induced diabetes. In contrast, when mice were given soluble forms of IL-18, they saw accelerated development of disease. By combining IL-18R expression with expression patterns of other known markers of destructive T cells the group hopes to map the patterns of this population to better understand its effect on the body, particularly on pancreatic islets. Experiments in mice are currently underway to evaluate whether these cells are present prior to onset, and if so, at what age. Once determined, this may be applicable to the human model as a way to predict disease.
In close collaboration with the Endocrinologist group at Children’s Hospital and Medical Center in Omaha, NE, lead by Dr. Kevin Corely, Dr. Sarvetnick hopes to offer patients a chance to participate in research, right in their own backyard! Recently diagnosed type I diabetes patients are recruited for the study. Their blood samples are taken back to the lab for detailed analysis of the immune system. Because the discovery of this population in the context of type I diabetes is novel, the group is still working to better understand the phenotype, function, and regulation of this unique population of T cells.
Much work has yet to be done on this population of cells and the goals of this research are reflective of that. The group hopes to better define the phenotype of this IL-18R+ CD8 T cell population in new onset diabetics and determine their involvement in the pathogenesis of type 1 diabetes.
Control NOD Mouse
Mouse Islets from control mouse (left) and Non-Obese Diabetic (NOD) mouse (left).
Green = Islet Cells Blue = Nucleus Pink = IL-18 receptor surface staining