Mechanism for Self-Repair of the Thymus Identified

An international research team led by scientists at the City of Hope reports that they have demonstrated a way in preclinical studies to boost thymic function after damage in preclinical studies. The results of the study “Recirculating regulatory T cells mediate thymic regeneration through amphiregulin following damage,” published in Immunity, outline their discovery of a specific type of regulatory T cell that can home back into the thymus and repair the organ when it’s damaged.

“Our discovery—the  regulatory T cell recirculation back to the thymus—promotes repair through a process that hasn’t been described before and represents a novel pathway to regeneration in the gland,” said lead author Andri Lemarquis, MD, PhD, staff scientist and group leader of the thymus research program in the laboratory of Marcel van den Brink, MD, PhD, president of City of Hope Los Angeles and National Medical Center, Deana and Steve Campbell Chief Physician Executive Distinguished Chair and senior author of the paper. “The findings open up a new translational angle for addressing thymic fatigue and damage.”

The human body faces a wide variety of threats from bacteria, viruses, and other dangers, such as cancer. T cells, made by the thymus, fight pathogens and malignancies through direct attack or by teaching other immune cells how to remove threats.

“Because there are so many different threats out there, we need an incredible diversity of these soldiers, or immune cells, to defend us,” explained Lemarquis. “But we also need some kind of control, so we don’t get a civil war in our body, like an autoimmune disease. This requires a school to teach these cells to protect us and that school is the thymus.”

Unfortunately, the thymus is highly susceptible to injury caused by stress, infections, aging, and cancer therapies.

“If you receive cancer therapies, your thymus is going to shrink,” said Lemarquis. “Without some help to grow again, patients won’t get what’s called immune reconstitution, in which new protective T cells are produced. Our work is trying to boost the thymus in patients who might lose this basic protection.”

Finding the key to regeneration

Lemarquis and the research team set out to explore mechanisms of thymus regeneration in two settings, cancer therapies and aging, which go together since aging cancer patients are highly susceptible to infection. The scientists first studied treatment-related injuries in murine models to understand how the thymus is damaged and under what conditions it begins to rebound. Then, they combined imaging and analyzing techniques with machine learning to identify specific pathways that are activated during regeneration.

What they found was a novel and previously undescribed population of thymic regulatory T cells (Tregs) that accumulate in the thymus after injury and secrete a growth factor called amphiregulin. Lemarquis and his collaborators were able to show that when these Tregs were added to the bloodstream intravenously, they found their way back to the thymus where amphiregulin then helped teach the thymus to regenerate and develop more T cells.

Next, they tested their findings in human tissue samples and saw the same results.

“We were able to go from mechanistic insights in mice to seeing that the same pathways were operating in the human setting,” noted Lemarquis. “There are a lot of adoptive cell therapies right now in the Tregs space, so that opens up the possibility for a translational approach where this subset of Tregs can be used to regenerate tissues, and specifically in the thymus and the immune system.”

He said the researchers were also surprised to find that the results extended to older mice, too, as it was believed that lost thymic function from aging may not be treatable.

“There are recent studies that show that if you lose thymic function in aging, you will have an increased rate of mortality due to a higher rate of cancers, infections and autoimmunity,” according to Lemarquis. “And what we could show was that when we transferred Tregs into aged mice receiving cancer therapies, we could even boost their function. It’s not only the young thymus that can be receptive to these signals to regenerate, but even the thymus in older patients receiving cancer therapies.”

From lab to life

The work outlined in the Immunity paper builds on a research program established in the late 1990s by Van den Brink to boost immune reconstitution in patients receiving cancer therapies, especially in the bone marrow transplantation field.

“He laid the groundwork over decades that provided us with the models, tools and data to get to where we are today,” pointed out Lemarquis. “There’s also been tremendous work on regulatory T cells, and we brought together these two fields to see if there’s something therapeutic that we can do in the setting of thymic injury. But brilliant minds before us led the way.”

Next, the researchers are delving into a large atlas of human thymic samples from cancer patients of different ages who have either thymic rebound or are in the degenerative phase to understand more about which pathways might intertwine with the regulatory T cells to further improve thymic function. They are also looking for other ways to apply their findings in a human setting, for example, by potentially using synthetic biology to modify T cells to overproduce amphiregulin or other beneficial factors.

“We have a thymic research program now at City of Hope, with computational biologists and postdoctoral scholars who are working on different projects, along with collaborators in the clinic who can help move our findings forward,” said Lemarquis. “I think there is great potential for Tregs and amphiregulin to be used therapeutically in patients receiving cancer therapies to ameliorate immune function.”

In addition to City of Hope scientists, the journal article included authors from Memorial Sloan Kettering Cancer Center, the University of Gothenburg in Sweden, Bambino Gesù Children’s Hospital in Rome, New York-Presbyterian Morgan Stanley Children’s Hospital, the University of Washington, Fred Hutchinson Cancer Center in Seattle, and the Weill Cornell Medical College in New York.