T cells show unexpected flexibility in the gut immune system
Researchers at Karolinska Institutet have identified new properties of CD4-positive T cells in the human intestines and liver. The cells display a combination of features from both the adaptive and innate immune systems, according to a study published in Science Advances.
In the immune system, CD4-positive T cells are typically described as so-called helper cells within the adaptive immune response, where they play an important role in building protection against new infections. The new study shows that these cells may be more versatile than previously recognised.
The researchers identified a specific population of CD4 T cells in the intestines and liver that have developed characteristics usually associated with the innate immune system. At the same time, they retain their adaptive function. According to the researchers, this hybrid identity appears to arise following long-term exposure to so-called persistent antigens, such as the cytomegalovirus.
“Our results show the breadth and flexibility of human CD4 T cells. They can adapt to the environment in tissues where they are encountering persisting antigens,” says Johan Sandberg, Professor at the Department of Medicine, Huddinge, Karolinska Institutet.
A hybrid of two defence systems
The identified cell population exhibits high functionality and can respond both to antigens and inflammatory signals. The researchers believe that these cells are likely to play a role in controlling viruses and microorganisms that are constantly present in the body’s tissues.
CD4 T cells are otherwise best known for their role in lymph nodes, where they help the body build a targeted immune response. The findings of the new study show that these cells can also adapt to the specific conditions found in peripheral tissues.
May contribute to a better understanding of intestinal disease
The research findings are primarily of a basic scientific nature but may also contribute to a better understanding of disease processes. In the study, the researchers observed that this type of T cell is less abundant in intestinal samples from patients with active inflammatory bowel disease (IBD).
“This may provide new clues as to what goes wrong in the regulation of the immune system in the intestinal mucosa in such diseases,” says Johan Sandberg.
In the next step, the researchers aim to investigate which signals drive the development of this type of CD4 T cell and how they are able to continue functioning despite persistent exposure to antigens.
The study was conducted within the framework of the IHOPE project using tissue samples from organ donors as well as intestinal biopsies. The first author is Tobias Kammann, a former doctoral student in Johan Sandberg’s research group, with support from doctoral student Isabel Voigt.
Publication
Intestinal resident effector–memory CD4 T cells on the adaptive-innate spectrum comprise IL-18 reactivity and adaptive CMV specificity
Tobias Kammann, Isabel Voigt, Nicole Wild, Efthymia Kokkinou, Curtis Cai, Takuya Sekine, Vera Nilsén, Whitney Weigel, Chris Tibbitt, Christopher Stamper, Anne Marchalot, John Bassett, Jyotsana Kaushal, Sabrina Ferreira, Elli Mouchtaridi, Elisa J. M. Raineri, Thomas R. Müller, Olga Rivera Ballesteros, Yu Gao, Akhirunnesa Mily, Sarah Adamo, Christian Constantz, Inga Rødahl, Demi Brownlie, Jakob Michaelsson, Jenny Mjösberg, Markus Birk, Marcus Buggert, Nicole Marquardt, Carl Jorns, Johan K. Sandberg, Science Advances, 15 May 2026, doi: 10.1126/sciadv.aed0028.