Study Suggests Possible Strategies to Halt or Prevent Type 1 Diabetes

Scientists have discovered how destructive immune cells gain access to insulin-producing cells and help cause diabetes.

The researchers demonstrated that to enter key areas of the pancreas known as the islets of Langerhans, immune cells known as T cells must recognize a marker on the surface of insulin-producing cells housed there. T cells play a key role in regulating immune response. Once inside the islets, T cells trigger the inflammation that can lead to destruction of the insulin-producing beta cells.

Understanding how T cell access to islets is controlled raises hopes for developing a therapy to re-educate the immune system to tolerate rather than attack the beta cells.

Image: T cell (blue) identifies the molecular signature of a dendritic cell (green).

Without insulin to turn food into fuel for cells, patients develop type 1 diabetes and are left dependent on insulin injections or an insulin pump. Unlike the more common form of the disease, known as type 2 diabetes, type 1 diabetes usually affects children and is sometimes called juvenile diabetes. Even with treatment, patients with type 1 diabetes are at risk for blindness, kidney failure and other complications.

For this study, the scientists modified T cell production in mice. They created strains of mice with only two types of T cells, each with different receptors. One population carried a receptor that recognized the insulin-producing beta cells and could cause diabetes. The other group was programmed to recognize a different antigen. The researchers could not induce the latter group of T cells to enter the islets.

They then created and tracked T cells with three types of receptors, receptors from T cells with a proven ability to enter islet cells and cause diabetes, those able to enter islets and cause inflammation, but not diabetes, and a third group of receptors with no connection to type 1 diabetes or islet cells. None of the T cells, even those with a demonstrated ability to cause diabetes in mice, could induce bystander T cells to enter the islet cells.

Finally, they tracked T cells carrying receptors from mice that naturally developed type 1 diabetes. They created mice with 17 new T cell receptors, five from the spleen of diabetic mice and 12 from T cells isolated in the islets of those diabetic mice. If the islets control T cells entry, then islets in the new mouse strains would be infiltrated by T cells with islet-derived, but not spleen-derived, receptors.

About 70 percent of the receptors that came from the islets could mediate T cell migration back into the islets, while none of the receptors that came from the spleen could do likewise. The islet-derived receptors were also linked to rapid development of diabetes, with one-third causing diabetes during the 10-week study.

The study results present possible new strategies to halt or prevent type 1 diabetes.

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References:
1. D. Vignali, et al. T Cell Islet Accumulation in Type 1 Diabetes Is a Tightly Regulated, Cell-Autonomous Event. Immunity, doi:10.1016/j.immuni.2009.07.008.
2. Image by Lawrence Berkeley National Library.