Nobel laureate makes regulatory T cells that last longer in the body, boosting clinical hopes

The Nobel Committee for Physiology or Medicine had treatments in mind when choosing its prizewinners this year. The award, split among three researchers, recognized the discovery of regulatory T cells, or Tregs, which stop accidental immune attacks against the body's own organs. Tregs could make powerful therapies for people with autoimmune disease -- if scientists could make large numbers of them that persist long enough in the body to work.

Now, one of the freshly minted Nobel laureates, Shimon Sakaguchi, tackles these challenges with a new method to make abundant, long-lasting Tregs. In the first of two papers published today in Science Translational Medicine, the University of Osaka immunologist and colleagues describe how their lab-generated cells effectively suppress immune responses in mice. In the second, he and other researchers made Tregs to treat a specific autoimmune skin disorder in mice and, setting the stage for a clinical trial, used a similar method to generate human Tregs from the blood of people with the painful condition.

"Many of us have been thinking about how best to unleash the potency of these regulatory T cells," says Qizhi Tang, an immunologist at the University of California San Francisco who was not involved in the work. "I think these are going to be very important studies to help catapult the field forward."

Conventional T cells sport receptors that recognize specific proteins, called antigens, typically on microbes or other invaders, and launch an immune attack. By contrast, Tregs are peacemakers. They recognize antigens including the body's own proteins and prevent immune cells from attacking tissues with those markers.

Scientists have tried various ways to harness the power of natural Tregs to dampen excessive immune reactions and prevent the friendly fire of autoimmune disease. One approach currently in clinical trials harvests the cells from human blood, multiplies them in a dish, and puts them back into patients. More recently, scientists have engineered artificial receptors, known as CARs, into these cells to target particular disease-specific antigens. But natural Tregs are scarce in blood and don't grow well in the lab, Tang notes. "It's a real bottleneck for the field."

Sakaguchi has gone a different route: generating Tregs from conventional T cells, including those that drive autoimmune disease. These cells are more common than Tregs in blood and are easier to grow in a dish.

Early on, his group and others used drugs and naturally occurring signaling molecules to make normal T cells switch on a key Treg-linked gene called Foxp3. The resulting induced Tregs (iTregs) dampen autoimmune activity -- but only briefly. Some "lose Foxp3 expression in a couple of days," says Masayuki Amagai, a co-author on the second paper published today and a dermatologist at Keio University.

Now, Sakaguchi and colleagues have found a way to help the reprogrammed cells endure. Their complex new recipe of signaling molecules and other compounds, described in one of the two new papers, not only increases Foxp3 expression, but induces epigenetic changes -- modifications to the structure of DNA and surrounding molecules -- intended to maintain Treg characteristics for longer.

To test their brand of iTregs, the researchers injected them into genetically engineered mice that were susceptible to gut inflammation. The result was durable protection against the inflammation. Even 6 weeks later, when iTregs generated with earlier protocols would have long since stopped working, most of the cells from Sakaguchi's team were still expressing Foxp3. Similar injections provided weeks of protection for mice primed to develop graft-versus-host disease -- an autoimmunelike condition in which transplanted stem cells attack the host's own tissues.

"It looks like [their protocol] is incredibly potent at creating stable long-lasting Tregs," says Adrian Liston, an immunologist at the University of Cambridge.

In the second paper, Sakaguchi, Amagai, and colleagues tested whether their iTregs could achieve more focused immunosuppression. Pemphigus vulgaris (PV) is a rare, potentially fatal autoimmune disease that occurs when the body attacks a protein called Dsg3 in the skin's epidermal layer, causing severe blistering. The team harvested tissue from mice engineered to make Dsg3-targeting T cells, converted those cells to iTregs, and injected them into mice with a PV-like disorder -- successfully suppressing skin irritation. Injections of iTregs made from the cells of normal mice (and thus not Dsg3 specific) were less effective.

The researchers also created iTregs from cells in PV patients' blood. Amagai says they are now working to adapt their approach for clinical trials testing the cells' safety in people.

The researchers suggest their strategy could be effective even if the disease-causing antigen is unknown. People with autoimmune conditions already have high numbers of T cells that recognize the disease-associated antigen -- so most iTregs generated from them would have that antigen specificity, too, the researchers argue. Still, University of Chicago immunologist Peter Savage thinks clinicians would still want a way to selectively increase the disease-specific iTregs compared with the rest.

The cells' long-term safety in people is uncertain. Even if the new iTregs are more stable than their predecessors, they might eventually revert to their original, pathogenic state, says James Riley, an immunologist at the University of Pennsylvania working on CAR Tregs. "That could actually exacerbate the disease rather than help it."

Nevertheless, Tang, who is developing engineered Tregs at a company she co-founded with Fred Ramsdell, another of this year's Nobel Prize winners, imagines combining the new approach with CAR and other technologies to fine-tune control of the immune system. "This is a superexciting field to be in right now."