When immune cells change sides: How Treg plasticity could shape future autoimmune treatment strategies.

Praespero
May 18
9 min read

Autoimmune disease is often described as the immune system attacking the body. That is a useful starting point, but it leaves out the deeper problem researchers must solve: what causes a normal immune response to become harmful, chronic, and difficult to control?

For Dr. Khashayarsha Khazaie and Dr. Fotini Gounari, Professors of Immunology at Mayo Clinic, that question sits at the centre of their Praespero-supported work on autoimmune disease with a special focus on inflammatory bowel disease, colon cancer, and the role of regulatory T cells and microbiota in the development of these diseases.

Featured in Praespero’s Impact Report as Mechanistic insight into de-regulation of inflammation and immunity by Tregs and microbiota, their research asks what happens when the immune system’s own mechanisms of balance begin to break down.

“We’re studying the difference between normal immunity and harmful immunity,” says Dr. Khazaie. “That can be studied in the context of various diseases in the intestine."

"For immunologists, the lower gastrointestinal track, small bowel and colon, are a very attractive subject of research," explains Dr. Gounari. "These organs house the largest number of immune cells and contain the highest densities of microbiota."

According to Dr. Khazaie our immune system is trained after birth through interaction with the gut microbiota.

"The composition of mother's microbes and diet shape our immune environment for life. Chronic diseases disrupt the healthy interaction between our immune system and gut microbiota pushing it into a spiral of harmful events. The key questions are how these interactions take place, how they become unbalanced, and how the healthy balance can be restored."

From symptoms to sources: understanding immune cell origins

The husband-and-wife team are a microcosm of what successful collaboration complimentary interests in bioscience research should look like.

Dr. Khazaie is especially interested in environmental root causes, including how environmental factors alter cell function and communication between cells. Dr. Gounari looks inside the cell to understand what happens when that environmental factor begins acting on it.

Before researchers can understand why immune regulation fails, they need to understand what immune cells are involved, how they become functional, and what internal mechanisms and external factors shape their behaviour and interactions.

“I’m interested in where immune cells start and the mechanisms that make them functional,” says Dr. Gounari. “If we don’t know this background, we cannot understand the major cause of autoimmunity. We can only understand the outcomes.”

That focus on causes rather than outcomes is central to our philosophy at Praespero.

The paradigm shift: regulatory T cells have functional plasticity

Dr. Khazaie and Dr. Gounari helped advance a finding that changed how researchers think about these cells: Tregs are not fixed in a single role. Under certain conditions, the same regulatory cell can change its function.

“The concept of plasticity was new,” says Dr. Khazaie. “When we realized that regulatory T cells, whose job is to make sure immune responses don’t go overboard, could change functions, we saw that the same cell could play on either side of the fence. It could be harmful, or it could be helpful in certain contexts. That was the plasticity, and it was very difficult to sell that idea.”

That is the unique angle of the work. Immune cells cannot always be sorted into simple categories of good or bad, protective or harmful. Their function depends on context. In a chronic inflammatory environment, even cells associated with regulation and balance may be pushed into altered behaviour.

When balance breaks: how inflammation reprograms cells

“The way I see immune plasticity is that you have a living cell in an environment that is not normal, that is pro-inflammatory,” says Dr. Gounari. “If that happens for a long time, these cells are reprogrammed.”In their research, Dr. Gounari explains, molecules in the inflamed environment can stimulate functions inside the cell and disturb the regulators that normally help keep the cell stable.

“If you disturb one of these regulators, you disturb some of these functions, and that is the plasticity,” she says. “We realized that the disturbed functions were changing the function of the regulatory T cells. If you mapped them, they would still look like regulatory T cells, but some of their functions were inhibited.”

“We realized that the disturbed functions were changing the function of the regulatory T cells. If you mapped them, they would still look like regulatory T cells, but some of their functions were inhibited.”

From insight to initiative: stabilizing cells for therapy

For patients and families, the most immediate question is what discoveries like this could mean for future prevention and treatment.

The answer has to be stated carefully.

This work can produce a patient-ready treatment protocol, since it points toward a major consideration for future autoimmune treatment strategies, especially approaches involving cell therapy or immune-cell manipulation.

If immune cells can change function, researchers need to understand what happens to those cells once they encounter a patient’s inflammatory environment.

A therapy needs to be judged by what a cell type is intended to do to prevent disease or to reverse disease. Scientists need to know whether that cell type is stable or changes function depending on its environmental context, whether it may be reprogrammed, and how its beneficial function might be preserved.

“It has a huge impact,” says Dr. Khazaie. “There is strong interest now in taking certain types of immune cells and putting them into a patient. It is now increasingly recognized that immune cells transferred into patients can change function over time. This has shifted attention toward strategies that manipulate and stabilize immune cell function, whether in endogenous or adoptively transferred cells, using targeted therapies or vaccination approaches to maintain beneficial functional states."

"There is strong interest now in taking certain types of immune cells and putting them into a patient. It is now increasingly recognized that immune cells transferred into patients can change function over time."

That insight has practical implications for how future therapies, including cell therapies, may be designed, according to Dr. Khazaie.

At Mayo Clinic, that line of investigation is already active. Researchers are acknowledging the uncertainty that comes with early translational science. And exploring how to stabilize cells given to patients for autoimmune disease.

“At this moment at Mayo Clinic, there is an initiative to provide therapeutic cells to patients and stabilize their protective functions for treatment of autoimmunity,” says Dr. Khazaie.

“There is always an element of uncertainty in interpreting new findings and testing new ideas. New discoveries are made and translated into medical practice only through curiosity, enthusiasm, diligence, and perseverance. Public support plays a critical role in enabling this process and should not be underestimated."

Plasticity: a double-edged sword for health

The careful promise of this work is that future treatment design may become more precise by accounting for the living, changing nature of immune cells.

Plasticity itself is not the enemy. In healthy immunity, the ability to respond differently to different threats is necessary. The danger comes when inflammatory responses become chronic and appear in the wrong setting.

“Plasticity is actually very important for maintaining health," says Dr. Khazaie. "If there is an acute viral infection, you need an inflammatory response to get rid of it. But you don’t want that inflammatory response to last for three months, because then you will get sick.”

He gives another example: fungal infection, where the body may require a more prolonged inflammatory response. The problem arises when that kind of response is too short in duration.

The careful promise of this work is that future treatment design may become more precise by accounting for the living, changing nature of immune cells.

“A chronic anti-fungal response, when it appears in the wrong context, can cause disease,” says Dr. Khazaie. “This is similar to the kind of inflammation that happens in cancer or in autoimmunity.”

The synergy of problem-solving and puzzle-solving

Praespero interrogates the autoimmune disease / cancer paradox often, with an underlying philosophy that a deeper understanding of root causes of autoimmune disease will potentially uncover answers to questions about cancer causes.

The project also reflects another part of Praespero’s philosophy: collaboration between researchers who approach disease from different vantage points.

Dr. Khazaie begins with disease models and patient-oriented problems.

Dr. Gounari compares those models to normal physiology and investigates the mechanisms that explain what went wrong.

“The collaboration becomes very strong because Khash has the ability to show me disease models that I can compare in depth with normal physiology,” says Dr. Gounari. “Then we can understand what went wrong in those disease models, which helps us understand and design cures. I see a synergy in this.”

“My motivation is to understand diseases and find solutions for them,” says Dr. Khazaie. “If I cannot relate my work to a disease, I am not motivated. Fotini’s motivation, from my perspective, is to solve puzzles.”

That difference is part of the strength of the collaboration.

“I can define the problem and address it,” says Dr. Khazaie. “Then she can go very deep into it and find mechanisms.”

“I can define the problem and address it. Then she can go very deep into it and find mechanisms."

That combination of disease focus and mechanistic depth is exactly the kind of scientific complementarity Praespero exists to encourage.

Autoimmune research needs specialists who can define urgent disease problems, specialists who can trace those problems into cellular and molecular mechanisms, and environments where those perspectives can meet productively.

“You can look at root causes of disease in two ways,” says Dr. Khazaie. “One is what happens inside the cell and, as a result, in the communication between cells. The other is the environment around the cell and what happens inside the cell as a result. What are the genetic, epigenetic, and transcriptional mechanisms? What happens from the gene to expression of the gene, to the phenotype, and to the change in function of the cell?”

“Recent biology has moved into the possibility of doing that in a spatial order," adds Dr. Gounari. "Understanding how cells communicate by analyzing the spatial organization of the microenvironment. This is a field where we are actively moving.”

Praespero Innovation Award: A chain reaction of impact

Praespero’s Innovation Award helped this work move forward at a critical stage. The idea of Treg plasticity was new, difficult to establish, and not immediately embraced.

Early support helped give the researchers room to complete preliminary findings, bring the work to publication, and build the evidence needed to pursue larger institutional funding.

“It is much easier to put flowers around a concept that has already been accepted than to come up with a completely new idea,” says Dr. Khazaie.

“That was a concept that was very new for us at the time, and it took a long time to get accepted. Now a lot of people are working on T cell plasticity and the plasticity of other immune cell types.”

“It is much easier to put flowers around a concept that has already been accepted than to come up with a completely new idea. T cell plasticity...was a concept that was very new for us at the time, and it took a long time to get accepted. ”

“Praespero’s support allowed us to finalize some of our preliminary observations and bring them to publication,” adds Dr. Gounari.

Dr. Khazaie describes the chain reaction.

“The funding allowed us to complete our preliminary findings, bring them to the level of a high-impact manuscript,” he says. “That opened the way to funding from the National Institutes of Health, which was renewed. The idea was new. People were reluctant to accept it. But Praespero trusted us, allowed us to make those ideas foolproof, and helped us get funding to continue the research.”

"The idea was new. People were reluctant to accept it. But Praespero trusted us, allowed us to make those ideas foolproof, and helped us get funding to continue the research.”

How collaborative science drives deeper discovery

Collaboration is revolutionary in the highly competitive biomedical research space. Praespero works to create the conditions where scientists can share ideas, compare perspectives, and pursue difficult questions in a field where competition can make open collaboration harder than it should be.

“People address questions differently,” says Dr. Khazaie. “They have different interests, different types of questions, and different talents. In order to be successful, you have to bring those things together. Complementarity is very important.”

Dr. Gounari sees false competition as one of the barriers that slows scientific progress.

“There are people who are frightened to share unpublished information,” she says. “They are frightened to discuss. I think that limits our ability to go one step forward.”

“There are people who are frightened to share unpublished information,” she says. “They are frightened to discuss. I think that limits our ability to go one step forward.”

“Praespero creates an environment where people come together and discuss without being afraid,” Dr. Khazaie adds. “It encourages people to be successful by working together.”

To learn more about the work of Dr. Khashayarsha Khazaie and Dr. Fotini Gounari, you can find the published articles on their research on pages 26 & 27 in our 2025 Impact Report.