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Putting the Brakes on the Immune System

11 June 2012 4:20 pm
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Arno Massee/Photo Researchers Inc.

Replacement. Researchers hope that immune-suppressing regulatory T cells will benefit organ transplant patients, but newly discovered versions of the cells might be a difficulty.

Your immune system protects you from bacteria and viruses, but you need specialized cells to protect you from your immune system. Overaggressive immune responses can cause everything from autoimmune diseases to organ rejection. Now, scientists have identified a new group of these specialized cells that seem to keep the immune system in check—at least in the short term.

The cells are a type of regulatory T cells, or Tregs. Researchers already know that Tregs serve as a mute button for the immune system. Last year, a team in the United States and another in Italy reported that infusions of Tregs forestall an often-fatal complication of bone marrow and stem cell transplants called graft-versus-host disease, in which immune cells in the transplant attack the recipient's cells. And several groups are planning clinical trials to determine whether Tregs curb the rejection of transplanted organs such as kidneys. To turn down the immune system, Tregs often latch onto a protein called TIM-3 on the surface of helper T cells—which orchestrate immune counterattacks against a pathogen—killing the helper T cell in the process.

Like the helper T cells they target, the newly identified Tregs have TIM-3 on their surface. Researchers led by transplant immunologist Terry Strom of Harvard Medical School in Boston found the new Tregs in abundance in mice that had recently received skin grafts. The cells gathered in the lymph nodes near the grafts and wriggled into the transplants themselves. In the culture dish, the TIM-3 sporting Tregs were better at shutting down immune cells than were ordinary Tregs, the researchers report online today in the Journal of Clinical Investigation.

To determine if this effect held in animals, the researchers transferred TIM-3 carrying Tregs into mice that had just received skin grafts. The Tregs appeared to tamp down the immune system, prolonging the survival of skin grafts from 13 days to 19 days. In the long term, however, Tregs lacking TIM-3 were superior, increasing the grafts' persistence to 120 days.

Strom and colleagues think that the Tregs that produce TIM-3 are less effective over the long term because they are dying off. "Nature has provided a system in which regulatory cells become increasingly potent but carry with them the seeds of their destruction," says Strom.

"Overall, they did a fine job," says transplant immunologist Thomas Wekerle of the Medical University of Vienna, who wasn't involved with the research. "It's another step toward understanding Tregs." In most situations, having Tregs that die off quickly makes sense, says immunologist Thomas Malek of the University of Miami in Florida. The cells can temper the immune response to a pathogen without causing potentially dangerous long-term immune suppression. "You don't want Tregs to dominate."

Strom says that the cells could be an obstacle for Treg therapy because they perish rapidly. He suggests it might be necessary to remove them before transferring Tregs into patients. However, researchers might also be able to capitalize on the cells' immune-suppressing prowess, says immunologist and transplant surgeon Matthew Levine of the University of Pennsylvania. "If you could turn off cell death but keep the regulatory function, that would make them more interesting for therapy."

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