Scientists develop a new organoid model to study thymus function

Researchers from the Organoid group have developed a new organoid model with which the thymus can be studied. The organoids are derived from mouse thymus tissue, specifically modeling thymic epithelial cells (TECs). These cells are responsible for training the immune system’s T cells to respond properly to pathogens.

It is the first laboratory model that allows long-term culture of TECs, providing new opportunities to study their function. Ultimately, this could also provide new insights into the treatment of patients with reduced thymus function. The study was published in Cell reports on March 27, 2024.

Our immune system protects us against pathogens such as viruses and bacteria. To effectively detect and eliminate these, different types of white blood cells are needed, including T cells.

Before they can do their work, T cells must be trained to attack only pathogens and not the body’s own cells. This happens in the thymus, a small organ behind the breastbone.

The “teachers” in this training process are called TECs. They present all kinds of molecules to the T cells and eliminate the molecules that do not respond properly. The end result is mature T cells entering the bloodstream, ready to respond to pathogens.

Researchers studying TECs need a way to grow these cells in the laboratory. The Organoid group has now succeeded in developing a new system: TEC organoids, based on mouse thymus tissue.

First author of the study Sangho Lim explains the advantage of these organoids over previous systems: “Previously, it was not possible to keep TECs in culture for a long time. This made it difficult to study them and conduct experiments. Our TEC organoids can be kept in culture for more than two years, allowing long-term experiments.”

Compared to other culture systems, the organoids are also a better representation of the diversity of TECs in the body. Specifically, two different subtypes of TECs exist, cortical and medullary TECs, depending on where they are present in the thymus. These subtypes also have specific functions in training T cells.

“By adding a different cocktail of molecules to the organoids, we can induce the cells to specialize into the cortical and medullary subtypes. Previously, it was difficult to get this diversity of TECs in culture,” says Lim.

Lim and his colleagues also confirmed that the TECs in the organoids were able to do their job: training T cells.

“We first mixed the organoids with immature T cells in culture. We then monitored their maturation by looking at the molecules CD4 and CD8 on the outside of the cells. In the body, immature T cells acquire and lose these molecules in a specific order. during their development, this corresponded nicely with what happened in our culture plates,” says Lim.

The researchers achieved similar results in mice born without a thymus. Lim adds: ‘These mice have very low numbers of mature T cells in the blood because they have no thymus to train them. When we transplanted our TEC organoids under their skin, we saw a very marked increase in the number of mature T cells. in their blood.”

It therefore appears that the TEC organoids were able to take over the function of the missing thymus by stimulating T cells to mature.

The mouse TEC organoids open new possibilities for scientists studying thymus and T cell maturation. From a clinical perspective, this is particularly relevant for patients with impaired thymus function, a condition that may result from specific cancer treatments or neonatal heart surgery.

“In the future, we may be able to explore TEC organoid transplantation as a treatment strategy to restore thymic function. But there is still a lot of work to be done before we get there,” Lim concludes.