VOLUME 13, NUMBER 03 • OCTOBER 19, 2001

Rockefeller researchers identify possible trigger for "killer T cells" to attack

Robert B. Darnell, Mithila Jegathesan and Matthew L. Albert propose a novel mechanism to explain how killer T cells know when to attack, and when to retreat.

Basic research often provides new insight into the underlying causes of disease. But sometimes the opposite is true, and the disease itself can teach scientists about fundamental principles in biology. In Professor Robert B. Darnell's laboratory, studies of the rare, debilitating neurological disease called paraneoplastic cerebellar disorder (PCD) have led to a deeper understanding of how both the brain and the immune system work.

PCD is associated with breast and ovarian cancer, and affects an average of one out of every 1,000 women. Unlike most cancer patients, however, persons afflicted with PCD successfully fight off their tumors. But, unfortunately, this victory comes at a price: the patients’ immune systems attack not only the tumors but a specific set of neurons in the brain, resulting in severe neurological symptoms, most notably the inability to coordinate bodily movements. This autoimmune attack on the brain occurs because PCD tumors, for unknown reasons, produce proteins normally restricted to the brain and thus provoke an immune response.

Darnell, who heads the Laboratory of Molecular Neuro-Oncology, began studying PCDs in 1992 as a model for understanding how these displaced proteins normally function in the brain. In addition, his laboratory set out to learn more about these patients’ remarkable tumor immunity, with the ultimate goal of reproducing this ability in cancer patients.

By 1998, their efforts had led to a radically new way of thinking about the immune system. Darnell, together with Rockefeller colleagues Matthew Albert, a clinical scholar, and Nina Bhardwaj, an associate professor for clinical investigation, demonstrated for the first time that "killer T cells," essential disease-fighting cells, target human tumors and offered a novel mechanism to explain how tumor-specific proteins, such as those in PCD tumors, alert killer T cells to their presence.

Now, Darnell, Albert and Mithila Jegathesan, a research assistant, show that the same mechanism responsible for inducing killer T cells to attack also instructs killer T cells about the body’s healthy cells, thereby preventing an autoimmune response.

Moreover, the new research points to the presence or absence of another set of immune cells, helper T cells, as being the trigger that signals killer T cells to either attack or withdraw.

"We are proposing an entirely new model to explain how killer T cells are regulated, one with important clinical implications," says Darnell, principal investigator of the study.

The findings, to be reported in the Nov. issue of Nature Immunology (published online on Oct. 9) may help scientists understand the breakdown in the immune system that leads to the development of juvenile diabetes, psoriasis and other autoimmune diseases. It may also explain 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 Albert, first author of the paper.

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 by Professor Ralph Steinman and the late Zanvil Cohn, 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 "central 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 the lymph nodes that drain these tissues that proteins not found in the thymus are scrutinized by the immune system. Autoimmune diseases result from a breakdown in this overall education process, called "peripheral tolerance."

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, Bhardwaj and Darnell, after studying tumor immunity in PCD patients, 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-proteins, 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 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 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 cell 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.

The new research immediately suggests new strategies for combating cancer and autoimmune diseases. "Eventually, it may be possible to manipulate an individual's immune system, triggering the activation of killer T cells for the attack of tumors and virus-infected cells," says Albert. "Our latest work indicates how killer T cells might conversely be turned off for the treatment of autoimmune diseases and for transplants."

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.