Scientists have discovered a "sense of touch" in immune cells
Activated T cells are able to perceive the stiffness of the surrounding tissue and rebuild their work in response. In a denser environment, they change shape, slow down movement, trigger DNA repair, and activate the genetic program characteristic of long-term immune memory cells. The results of the study were previously published in the journal Nature Immunology.
The discovery complements the traditional understanding of the immune system. Previously, it was believed that the fate of T cells after infection is mainly determined by chemical signals: antigens, cytokines and other molecules. The new work shows that the physical properties of the environment can also influence what immune cells become and how long they last in the body.
How immune memory is formed
After infection, some CD8+ T cells destroy the affected cells and help the body cope with the infection. Most of them then disappear, but some turn into memory cells.
A special place among them is occupied by tissue-resident memory T cells. Unlike cells that circulate through the blood and lymphatic system, they remain in the skin, lungs, intestines, liver, and other organs. If the pathogen returns, these cells can quickly recognize the threat and trigger a local defense reaction.
Until now, the formation of such cells was primarily associated with biochemical signals. The authors of the new work suggested that the path that the T cell passes through the tissue may also be important. Different organs differ significantly in density, structure, and ability to resist deformation. Therefore, the immune cell has to not only recognize molecular signals, but also literally squeeze between the fibers of the extracellular matrix.
Judith Mandl, Professor of the Department of Physiology at McGill University, is the lead author of the study.
The results show that T cells can "sense" their surroundings and adapt to them.
According to her, the physical environment in this case becomes an active factor capable of determining the behavior of immune cells.
How scientists tested the "sense of touch"
The researchers worked with activated CD8+ T cells from mice and humans. The cells were placed in three-dimensional collagen gels that mimicked tissues with different stiffness. One type of matrix was soft, the other was about three times more resistant to deformation.
At the same time, scientists tried to keep the other characteristics of the environment unchanged. This made it possible to check whether the observed reactions were caused by mechanical stress or differences in chemical composition.
In hard collagen, T cells moved more slowly, became larger, and acquired a more rounded shape. The size and shape of their cores also changed. After a day, these differences turned out to be significantly more noticeable than after eight hours, that is, the reaction intensified as the cell remained in a dense environment.
At the same time, the production of lamin A and C proteins increased, forming a kind of scaffold around the cell nucleus. In most leukocytes, the content of these proteins is relatively low: the soft core helps them pass through the narrow spaces between tissues. However, under increased stress, T cells probably have to strengthen the shell of the nucleus to protect the genetic material inside.
A similar reaction was found in both mouse and human CD8+ T cells. In experiments with human cells, the blood of healthy volunteers aged 29 to 38 years was used. Depending on the specific analysis, the number of donors ranged from five to 11 people.
What happened to the DNA of the cells
Movement through a dense environment turned out to be associated not only with a change in the shape of T cells. The researchers found signs of DNA damage and the subsequent triggering of its repair mechanisms.
The proportion of cells with a high level of the double-stranded DNA break marker in the hard gel was 3.1 times higher than in the soft gel. The activity of one of the proteins controlling the response to damage to genetic material increased 1.6 times.
At the same time, the cells temporarily slowed down their division. In a hard environment, 53% of T cells were in the first phase of the cell cycle, while in a soft environment, 27% were. The total number of cells in dense collagen turned out to be about half that, but the scientists did not find a noticeable decrease in their viability. The mechanical load didn't just make it difficult to move. It forced T cells to redistribute resources: slow down reproduction, strengthen the nucleus, and repair DNA damage.
How the rigidity of the environment has changed the work of genes
The scientists found the most significant differences when analyzing the activity of genes. More than 9.1 thousand genes with different expression levels were identified between T cells from soft and hard gels. The work of 3.6 thousand of them in a dense environment was more than doubled.
The changes affected genes related to movement, restructuring of the cellular skeleton, cell cohesion, DNA repair, and transmission of mechanical signals. The main result was the inclusion of a program resembling the state of tissue-resident memory T cells. Of the 55 discovered genes included in the main characteristic of such cells, 42 reacted to changes in environmental hardness.
In particular, in dense collagen, the activity of genes that help T cells return to the bloodstream and lymphoid organs decreased. At the same time, the work of genes related to the fixation of cells in tissues and their transformation into local immune "guards" increased.
The mechanical load also affected the regulatory proteins Runx3, Hic1, and KLF2. The first two are involved in the formation of memory tissue cells, and a decrease in KLF2 activity helps T cells stay inside organs rather than returning to the bloodstream. The researchers found a similar increase in RUNX3 in human CD8+ T cells.
The cells have memorized the mechanical impact
Some changes persisted even after the cells were removed from the tough collagen and placed in a normal liquid medium for a day. This indicates the possibility of a kind of mechanical memory, although its duration and reversibility have yet to be determined.
In another part of the experiment, mouse T cells treated in soft or hard gel were injected into animals. After seven days, cells that had previously been in a dense environment were almost twice as likely to acquire signs of tissue-resident memory cells.
In addition, the scientists compared the mechanical properties of different organs of mice. The liver, lungs, kidneys, and salivary glands were about 10 times tougher than the lymph nodes and spleen. After a viral infection, the stiffness of the spleen increased approximately six-fold at the peak of the immune response. The authors suggested that mechanical changes in lymphoid organs during the disease may prepare T cells in advance for the transition to denser tissues.
Why the discovery may be important for cancer treatment
The mechanosensitivity of T cells is of interest for oncology. Many solid tumors are surrounded by a dense extracellular matrix, which makes it difficult for immune cells to enter. Even if a T cell recognizes a tumor, it needs to get to the malignant cells and retain the ability to move in a harsh environment.
Understanding how T cells adapt to such a load may help in the future in the creation of immunotherapy. For example, researchers will be able to try to prepare cells in advance for a dense tumor environment or change the mechanisms responsible for their movement, survival and fixation in tissues.
In 2026, another group of scientists showed in Nature Communications that the extracellular matrix in triple-negative breast cancer is able to limit the penetration of T cells and support immune suppression. Changing certain carbohydrate compounds on matrix proteins improved the access of T cells to tumor tissue and reduced the signs of their depletion. Together, these studies show that the tumor environment should be considered not only as a physical shell, but also as a full-fledged participant in immune processes.
However, the new study does not yet offer a ready-made treatment method. The main experiments were carried out on mouse cells, in artificial collagen matrices and on animals. Only a part of the identified reactions were confirmed on human cells outside the body.
What remains to be seen
The main unresolved issue remains the mechanism that allows the T cell to measure the hardness of the medium. The authors tested several known mechanosensitivity pathways, including YAP and TAZ proteins, integrins, phospholipase cPLA2, myosin II, and lamins A and C. None of them turned out to be the main switch of the tissue memory program.
Scientists also need to establish how long the mechanically formed state persists and whether it can be safely controlled. Strengthening tissue immune memory can be useful in infections and cancer, but the same cells can support chronic inflammation, allergic reactions, transplant rejection, and some autoimmune diseases.
Therefore, potential therapy can develop in two opposite directions: to strengthen the fixation of T cells in tumors and foci of infection, or to interfere with their long-term preservation in healthy tissues, which they mistakenly attack.
So far, the research is primarily changing the fundamental understanding of immunity. It shows that the fate of T cells is determined not only by a set of chemical signals. The physical world through which these cells have to move may also be important for the formation of long-term protection.
Переведено сервисом «Яндекс Переводчик»
