First-Ever Findings from JDRF-Funded Scientists Provide Evidence about How Killer T Cells Form Their Fatal Attraction with Beta Cells

A new study supported by JDRF and additional funding sources in the United Kingdom revealed groundbreaking information about the mechanism responsible for the autoimmune attack that is a hallmark of type 1 diabetes (T1D). Two groups of prominent researchers, from Cardiff University School of Medicine in Wales and King’s College London, used an actual T cell that was replicated or “cloned” from a patient with T1D to literally get “a view to a kill,” meaning that they were able to produce a visual image of the molecular interactions that mediate the fatal autoimmune attack.

To get a molecular-level view, the researchers were aided by x-ray crystallography, a technique that uses x-rays to gather information about the structure of molecules that have been crystallized. With this technology, they were able to see just how a specific type of T cell1 manages to encounter insulin-producing beta cells in the pancreas. Learning about how this deadly encounter takes place can help to advance the understanding of how T1D develops in individuals.

The research, led by Andrew K. Sewell, Ph.D., and published online in the January 15, 2012 issue of Nature Immunology, examined the way in which the cells responsible for attacking beta cells, called CD8 killer T cells, actually latch onto the beta cells. This latching on, referred to as the “docking mode,” is accomplished via the assistance of a network of receptors. In previous studies, docking modes have been described in a different type of T cell in other autoimmune disease settings. However, Dr. Sewell’s work is the first to provide information on how this happens with killer T cells in T1D.

Dr. Sewell and collaborators investigated the interaction between certain receptors on T cells (TCRs2) and their target—the beta cells. Specifically, they looked at how TCRs recognize and make contact with a protein fragment on the beta cell’s surface (MHC3). What’s important to understand here is that the advance in knowledge about the interaction of these molecular players represents a critical finding in T1D science.

The researchers were surprised by the results, which showed that the attraction of TCRs to MHC is weaker than expected, and thus the contact between killer T cell and beta cell is also weak. Importantly, the researchers suggest that it may take an additional factor, such as an infection, to cause the killer T cell–beta cell interaction to become destructive to the beta cell.

“The findings of Dr. Sewell and his colleagues comprise a significant discovery that clearly characterizes the recognition between killer T cells and beta cells in the development of type 1 diabetes,” states Simi T. Ahmed, Ph.D., scientific program manager of immune therapies at JDRF. “This work paves the way for a more intelligent design of therapeutics that could aim not only to interfere with the interaction between a killer T cell and its target, but also to prevent it from becoming activated as a result of this interaction and go on to attack the beta cell.”

1 a critical immune system component involved in the development of type 1 diabetes
2 T cell antigen receptors (TCRs)
3 major histocompatibility complex (MHC)

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