Immune cells as squatters

Resident T cells (purple) survive radiation and chemotherapy in some patients. Donor cells (pink and green) are thus primarily found in the bloodstream.

Image: Daniela Leitner/Science Immunology

Human immune cells not only circulate in the blood, but can also occupy certain tissues and sometimes remain there for years. A research team led by immunologist Prof. Dr Christina Zielinski discovered this phenomenon by examining patient samples after stem cell transplantation. In addition, the researchers were able to characterize the special properties of tissue-resident immune cells in more detail. The results were published in "Science Immunology".

When pathogens enter the human body, a large number of immune cells are quickly on hand to recognize and destroy the invaders. Among them are T cells, a type of white blood cells that can directly recognize invaders such as viruses or bacteria.

However, new results indicate that the name "blood cells" for this group is somewhat misleading. "We were able to show that T cells sometimes remain in the skin for years and are thus optimally adapted to the local situation," says Christina Zielinski.

Most T cells remain in the tissue

"It was long assumed that T cells circulate only briefly through the tissue, for example, to fight an infection, but do not linger there any longer, instead migrating directly back into the bloodstream," Zielinski explains. However, her team's results demonstrate that the majority of T cells remain in the tissue long term, with far fewer actually circulating the body. "This also suggests that blood samples might tell us very little about how good a person's immune defenses are," Zielinski says.

In order to track T cells in humans and find out which cell is where and how long it stays there, the team had to use a trick. "We studied samples from patients who had received allogeneic stem cell transplants," Zielinski said. That means these patients had their own immune system destroyed by chemotherapy and radiation and it was then rebuilt with the help of blood stem cells from a donor. For some diseases, especially leukemia, this may be the only cure.

The researchers examined skin biopsies and blood samples taken two to three years after stem cell therapy. This allowed them to determine whether the T cells they found derived from patient or donor. "We determined the genetic fingerprint of individual cells for this purpose," Zielinski explains. This enabled her to show that half of the T cells in the skin originated from the patients themselves, whereas in the blood T cells almost exclusively from the donors were found. Accordingly, the patient's own immune cells survived for years in the skin tissue. However, only about a quarter of the recipients of stem cell therapy showed this profile; the immune system had been completely replaced in the remainder.

Possible consequences for transplants

"It is still unclear why some patients retain their own immune cells," says Zielinski. She also says that more research is needed into what effects this has. She suspects that the resident T cells may have a protective function. "I think of it like squatting: The donor cells then can't get into the tissue because that's already occupied by the patient's own T cells." Therefore, they would not be able to cause inflammation. The resident T cells found, she said, were of an anti-inflammatory variety, supporting this thesis.

Her research group will now focus on the effects in liver transplants. Here, too, the question is whether T cells remaining in the tissue - in this case from the donor - could possibly protect the organ from rejection.

Insights into the immune system

"Resident T cells are optimally adapted to the skin and can thus specifically support its barrier function in defending against pathogens," Zielinski says. Using modern RNA analysis of individual cells (single-cell RNA sequencing), the research team was also able to identify that sometimes memory T cells leave the tissues again and can then be found in the bloodstream. "This could serve to communicate with other organs," Zielinski speculates. The genetic markers for resident T cells found by her team can now be used both to find them more easily and to study their function in more detail.

Teamwork

The study was conducted under the leadership of Christina Zielinski. She worked at the Technical University of Munich until 2020 before accepting a call to the Carl Zeiss Foundation-funded Professorship of Infection Immunology at Friedrich Schiller University Jena. At the Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute - she heads the Department of Infection Immunology. Other members of her team conduct research at the Technical University of Munich with the Klinikum rechts der Isar, the Helmholtz Zentrum München and the German Center for Infection Research.

The work was funded by the German Research Foundation (DFG) under the Collaborative Research Center FungiNet and the Cluster of Excellence Balance of the Microverse, among others. It was also supported by the Leibniz Center for Photonics in Infection Research which is funded by the German Federal Ministry of Education and Research.