Scientists at the University of Cambridge have discovered that regulatory T (Treg) cells, a type of white blood cell, exist as a single large population of cells that constantly move throughout the body looking for and repairing, damaged tissue. This finding from their study carried out in mice, overturns traditional thinking that regulatory T cells exist as multiple specialist populations that are restricted to specific parts of the body. The discovery has implications for the treatment of many different diseases, because almost all diseases and injuries trigger the body’s immune system.

“We’ve uncovered new rules of the immune system,” said Professor Adrian Liston, PhD, at the University of Cambridge department of pathology. “This ‘unified healer army’ can do everything—repair injured muscle, make your fat cells respond better to insulin, regrow hair follicles. To think that we could use it in such an enormous range of diseases is fantastic: it’s got the potential to be used for almost everything.”

Liston is a senior author of the team’s published paper in Immunity, titled “The tissue-resident regulatory T cell pool is shaped by transient multi-tissue migration and a conserved residency program,” in which they stated, “… we performed a systematic analysis of the Treg cell population residing in non-lymphoid organs throughout the body, revealing shared phenotypes, transient residency, and common molecular dependencies … This work suggests common regulatory mechanisms may allow pan-tissue Treg cells to safeguard homeostasis across the body.”

The body’s tissues are the site of many important immunological reactions, but how the immune system is controlled at these sites isn’t well understood, the authors noted. “Our understanding of the immune component of non-lymphoid tissues is “relatively limited,” they pointed out, and “often extrapolated from the lymphoid tissues.”

Most white blood cells attack infections in the body by triggering an immune response. In contrast, regulatory T cells act like a unified healer army whose purpose is to shut down this immune response once it has done its job—and repair the tissue damage caused by it. For their study the researchers analyzed the regulatory T cells present in 48 different tissues in the bodies of mice. Their results revealed that the cells are not specialized or static, but move through the body to where they’re needed.“It’s difficult to think of a disease, injury or infection that doesn’t involve some kind of immune response, and our finding really changes the way we could control this response,” said Liston.

Current anti-inflammatory drugs treat the whole body, rather than just the part needing treatment. The researchers say their newly reported findings mean it could be possible to shut down the body’s immune response and repair damage in any specific part of the body, without affecting the rest of it. This means that higher, more targeted doses of drugs could be used to treat disease—potentially with rapid results.

Liston added, “Now that we know these regulatory T cells are present everywhere in the body, in principle we can start to make immune suppression and tissue regeneration treatments that are targeted against a single organ—a vast improvement on current treatments that are like hitting the body with a sledgehammer.”

Dr Oliver Burton, lead author on the study, uses spectral cytometry to analyse anti-inflammatory regulatory T cells from different tissues.
Oliver Burton, lead author on the study, uses spectral cytometry to analyse anti-inflammatory regulatory T cells from different tissues. [Louisa Wood, Babraham Institute]
Using a drug they have already designed, the researchers’ experiments in mice showed that it’s possible to attract regulatory T cells to a specific part of the body, increase their number, and activate them to turn off the immune response and promote healing in just one organ or tissue. Among their findings, the team highlighted that regulatory T cells across different non-lymphoid tissues share a common phenotype. “Using high-parameter flow cytometry, we found unified phenotypes for tissue Treg cells in the nonlymphoid non-gut tissues, coupled with common molecular dependencies and shared T cell receptor (TCR) clonality,” they stated. “Our data further showed that tissue residency was generally short, on the order of 3 weeks, and extracted tissue Treg cells were tissue-agnostic on re-entry.”


Liston further commented, “By boosting the number of regulatory T cells in targeted areas of the body, we can help the body do a better job of repairing itself, or managing immune responses. There are so many different diseases where we’d like to shut down an immune response and start a repair response, for example autoimmune diseases like multiple sclerosis, and even many infectious diseases.”

Most symptoms of infections such as COVID are not from the virus itself, but from the body’s immune system attacking the virus. Once the virus is past its peak, regulatory T cells should switch off the body’s immune response, but in some people the process isn’t very efficient and can result in ongoing problems. The new finding means it could be possible to use a drug to shut down the immune response in the patient’s lungs, while letting the immune system in the rest of the body continue to function normally.

In another example, people who receive organ transplants must take immunosuppressant drugs for the rest of their lives to prevent organ rejection, because the body mounts a severe immune response against the transplanted organ. But this makes them highly vulnerable to infections. The new finding helps the design of new drugs to shut down the body’s immune response against only the transplanted organ but keeps the rest of the body working normally, enabling the patient to lead a normal life.

The researchers aim to establish a spin-out company, with a view to test out their findings through future clinical trials. Noting limitations of their study, the team acknowledged that their reported work was carried out exclusively in mice, and as such,”further tissue-based analysis of human Treg cells is needed to determine whether features differ in humans,” they stated.

And in conclusion, they wrote, “Together, these results demonstrate that the tissue-resident Treg cell pool in most non-lymphoid organs, other than the gut, is largely constituted by broadly self-reactive Treg cells, characterized by transient multi-tissue migration. This work suggests common regulatory mechanisms may allow pan-tissue Treg cells to safeguard homeostasis across the body.”

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