Researchers Discover Possible Trigger For "Killer T Cells" To Attack

"We are proposing an entirely new model to explain how killer T cells are regulated, one with important clinical implications," says Robert B. Darnell, M.D., Ph.D., head of Rockefeller's Laboratory of Molecular Neuro-Oncology and principal investigator of the study.

The new research may help scientists understand the breakdown in the immune system that leads to the development of lupus and other autoimmune diseases. It may also offer new insight into how cancer cells and viruses, such as HIV, evade the immune system. What's more, knowledge of how killer T cells are turned "on" or "off" ultimately may allow researchers to manipulate this switch for the treatment of these and other diseases.

"Our work demonstrates a new mechanism of killer T-cell regulation and suggests a novel therapeutic approach for shutting off these cells in patients with autoimmune disorders and in patients receiving organ or bone-marrow transplants," says Matthew Albert, M.D., Ph.D., first author of the paper and a clinical scholar at Rockefeller.

Killer T cells play a vital role in the immune system. When turned on or activated, they can target and destroy cancerous cells and cells harboring viruses. Specialized cells called dendritic cells, first discovered at Rockefeller in the 1970s, present pieces of proteins or antigens to the killer T cells in order to alert them to the presence of the intruders. To perform this important function, however, the T cells first need to be taught about the body?s own proteins, such that potentially self-reactive T cells are prevented from killing the body's own cells. This "education," or protein surveillance, occurs in the thymus gland, a small organ situated behind the top of the breastplate, and is referred to by scientists as "tolerance."

But what about proteins not found in the thymus, for example those unique to the pancreas or skin? Recent studies in mice have shown that another round of education occurs in the various other tissues of the body, collectively known as the periphery. It is in these tissues that proteins not found in the thymus are scrutinized. Autoimmune diseases result from a breakdown in this overall education process.

While T-cell activity in the thymus is well understood, the molecular and cellular details of how T cells are regulated in the periphery only recently have begun to emerge.

In 1998, Albert, Darnell and another Rockefeller scientist, Nina Bhardwaj, M.D., Ph.D., an associate professor for clinical investigation, solved one of the most pressing mysteries of killer T cell activation in the periphery: namely, how do tumor cells and virus-infected cells deliver their information to the immune system so that it can mount an attack? Scientists already knew that dendritic cells present killer T cells with pieces of viral, tumor or self-antigens, but it remained unclear how these antigens, which normally reside inside of cells, are captured by the dendritic cells.

The researchers showed that a type of cell suicide called apoptosis (pronounced a-puh-TOE-sis) provided the solution to the riddle. They discovered that apoptotic cells signal the dendritic cells to chew them up and to present the remaining bits and pieces to killer T cells. This finding was significant because apoptosis was previously thought to play no role in the immune system.

"It turned out that apoptosis was not an end in itself, but a beginning," says Darnell.

Now, Albert and Darnell have taken this work one step further by providing evidence for the role of dying cells in in both killer T cell activation and tolerance. Moreover, the current paper proposes a new mechanism to explain how the T cells determine the path they should take.

Previous research suggested that killer T cells are activated by two specific molecular signals. In addition, these studies argued that the trigger for T-cell activation is the maturation of the dendritic cell.

The new theory, however, proposes that a third signal - helper T cells - acts like a switch to trigger the T-cell activation pathway. "Previously it was believed that an immature dendritic cell triggered T-cell tolerance and a mature dendritic cell signaled T-cell activation," says Albert. "Our studies suggest that the mature dendritic cells is actually required for both activation and tolerization and points to the presence or absence of helper T cells as being the critical trigger."

Helper T cells are known to play a role in the production of antibodies, a function of the immune system. Scientists thought that these cells also aided killer T cells in some way, but this role was unclear until now.

Knowledge of this switch may ultimately lead to new ways of manipulating the immune system for the treatment of several diseases. For example, to treat cancer, researchers imagine boosting the body's killer T cells, essentially turning them on, by first mixing dendritic cells with a sample of dying tumor cells in a test tube, then reinjecting the mixture back into the patient - an experimental technique referred to as immunotherapy. And to treat autoimmune diseases or improve organ and bone- marrow transplant procedures, the goal would be to switch off the killer T cells that are erroneously attacking healthy cells.

Darnell's lab at Rockefeller focuses on both immunology and neuro-oncology. This unusual combination arose out of studies on a rare debilitating neurological disease called paraneoplastic cerebellar disorder (PCD). In 1998, Albert and Darnell discovered that these patients harbored killer T cells that were capable of targeting their tumors, resulting in naturally occurring tumor immunity. The reason for this uncommon occurrence is that PCD tumors produce brain proteins, thus allowing the immune system to recognize the tumor cell as an invader. Hence, the killer T cells attack the tumors but, unfortunately, begin to target parts of the brain as well, resulting in neuronal degeneration. The researchers' discovery of the role of apoptosis in providing a source of antigen for dendritic cells grew out of this work.

The current study was funded by a grant from the National Institutes of Health, the National Cancer Center, the Susan G. Komen Breast Cancer Foundation and the Burroughs-Wellcome Fund.

John D. Rockefeller founded Rockefeller University in 1901 as The Rockefeller Institute for Medical Research. Rockefeller scientists have made significant achievements, including the discovery that DNA is the carrier of genetic information. The University has ties to 21 Nobel laureates, six of which are on campus. Rockefeller University scientists have received this award for two consecutive years: neurobiologist Paul Greengard, Ph.D., in 2000 and cell biologist Günter Blobel, M.D., Ph.D., in 1999, both in Physiology or Medicine. At present, 33 faculty are elected members of the U.S. National Academy of Sciences. Celebrating its Centennial anniversary in 2001, Rockefeller - the nation's first biomedical research center - continues to lead the field in both scientific inquiry and the development of tomorrow's scientists.