Good Cells Going Bad May Lead to Diabetes

By Jeffrey Norris

New clues to type 1 diabetes and other diseases have come to light thanks to UCSF researchers who explore how the immune system normally refrains from attacking the body’s own tissues. A type of protective cell goes over to the dark side, they discovered. The immune system is tuned to attack molecules found on infectious disease pathogens. But in autoimmune diseases the immune system attacks the body’s own molecules and cells. A type of cell called a regulatory T cell normally protects against autoimmune attack. But now UCSF scientists have found that regulatory T cells can be transformed from protective to destructive cells. It’s conceivable that bouts of infection and inflammation might sometimes tip the balance toward autoimmune disease in susceptible individuals, the researchers suggest.

Jeffrey Bluestone

The UCSF researchers caused mice to develop diabetes by injecting them with a specific subset of regulatory T cells. Most regulatory T cells make a supply of a protein molecule called FoxP3, and these cells are protective. But to trigger diabetes the researchers injected only a subset of regulatory T cells -- those that had stopped making FoxP3. The natural presence or absence of this protein appears to act as a control mechanism, one that might be tipped off-balance in human diabetes and in some of the more than 80 or so known autoimmune diseases. The consensus among scientists is that type 1 diabetes, sometimes called juvenile onset diabetes, is indeed an autoimmune disease. The immune system attacks insulin-secreting islet cells of the pancreas. However, the precise mechanisms involved remain the subject of intense research. Techniques to fight diabetes and other autoimmune disease by boosting the number of regulatory T cells already are being explored by UCSF scientists and by researchers elsewhere. The newly reported findings support the importance of this approach, suggest new ideas for maintaining protection, and point to a strategy for identifying individuals who might be susceptible to autoimmune disease. UCSF’s Jeffrey Bluestone, PhD, head of a national consortium called the Immune Tolerance Network, led the UCSF laboratory team. The researchers present their results in the July 26 online edition of Nature Immunology. Most of the reported experiments were done by three postdoctoral fellows, Xuyu Zhou, PhD, Samantha Bailey-Bucktrout, PhD, and Lukas Jeker, MD, PhD. A popular idea among scientists is that either insufficient numbers of regulatory T cells or defective regulatory cells might be responsible for autoimmune disease. In fact, there is one extreme example of this. In rare cases an infant is born lacking any regulatory T cells. Such an infant requires a complete bone marrow transplant to provide the cells, or else a massive autoimmune response will kill the child within months. But it’s not just the number of cells that’s important; it’s the roles they play. The UCSF researchers found that regulatory T cells can shift roles. They identified a balancing mechanism that can reach a tipping point. “We believe the data suggest that not only can the regulatory T cells be dysfunctional and fail to suppress an autoimmune response, but they also can actively become disease-causing cells,” Jeker says. Cells that appear to be protective regulatory T cells can turn into a different type of cell, called a memory T cell, which attacks its molecular target instead of protecting the target from attack. The switch occurs when regulatory T cells stop making FoxP3. The experiments to track loss of FoxP3 and the changes that result became possible only after Zhou generated a new strain of mice especially engineered for the this purpose. Transferring regulatory T cells that had spontaneously lost FoxP3 into healthy mice was sufficient to cause diabetes. “There is no doubt that regulatory T cells are critical for survival and for controlling the immune system,” Jeker says. “There also is no doubt that FoxP3 plays a major role in maintaining these cells.” It may be possible to develop tests to gauge an individual’s susceptibility to autoimmune disease through the measurement of FoxP3 in regulatory T cells, Jeker says. Bluestone heads the Diabetes Center at UCSF. Researchers at the Diabetes Center are pioneering innovative islet cell transplantation techniques to replace insulin-secreting cells that are lost because the immune system has destroyed them. These UCSF scientists also are striving to better understand how type 1 diabetes arises and how to prevent it. Clinical trials are being planned at UCSF and elsewhere in which researchers will treat type 1 diabetes by removing patients’ regulatory T cells, expanding their numbers by growing them outside the body, and then re-infusing them into the patient. The new study points to the additional importance of stabilizing existing regulatory T cells and preventing them from becoming attackers. Certain naturally occurring molecules, called cytokines, are secreted by immune cells and appear to affect the stability of regulatory T cells, Jeker says. Cytokine secretion resulting from an inflammatory response to infection might sometimes be a trigger for destabilization leading to autoimmune disease, Jeker speculates. “There normally are limits on the immune system when it comes to fighting infectious intruders and cancers. If you fight too much you might start attacking your own tissue. The immune system is very powerful, and you have to control it. A delicate balance needs to be maintained.” Small-molecules drugs might be used to affect this balance, he suggests.

Instability of the Transcription Factor Foxp3 Leads to the Generation of Pathogenic Memory T Cells in Vivo

Xuyu Zhou, Samantha Bailey-Bucktrout, Lukas T Jeker, Cristina Penaranda, Marc Martínez-Llordella, Meredith Ashby, Maki Nakayama, Wendy Rosenthal and Jeffrey A Bluestone

Nature Immunology
(published online July 26, 2009)


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