June 20, 2024

Thymus boost |  Max Planck Society

Thymus boost | Max Planck Society

Max Planck researchers identify epithelial stem cells that control thymic growth at different stages of life.

Many immune cells, which are crucial to our immune system, develop in early life and into adolescence in a small organ next to our heart: the thymus. But with age the thymus shrinks and its function diminishes and thus the number of powerful immune cells decreases. Max Planck’s research groups from Freiburg and Würzburg have now identified the processes that control the development and formation of thymic tissue over the course of life. They also came across potential therapies for age-related shrinkage of the thymus and for autoimmune diseases.

The thymus is a central organ of the immune system. This is where those T cells are formed that, as killer cells, recognize and destroy virus-infected or degraded cells, as well as the so-called helper T cells, which help the body create antibodies.

Over the past few decades, Thomas Bohm’s research group at the Max Planck Institute for Immunology and Epigenetics in Freiburg has been able to identify the genetic switches required in the thymus for T-cell maturation. The so-called thymic epithelial cells, which attract T-cell precursors and bring them to maturity, are necessary here. T cells learn to distinguish between diseased cells, healthy cells, and foreign cells from their own. With it, you can detect and eliminate unwanted structures and prevent autoimmune diseases. Previous work in Thomas Bohm’s laboratory has shown that the two major forms of thymic epithelium arise from bipotent progenitor cells. However, it is not yet clear whether there is more than one type of precursor and how many subspecies in which the precursors are distinguished.

Lineage analysis identifies progenitor cells of the thymic epithelium

In cooperation with Dominic Green Laboratory (formerly the Max Planck Institute for Immunobiology and Epigenetics, now the Max Planck Research Group at the University of Würzburg), a specialist in single-cell molecular analysis, researchers have now molecularly recorded the astonishing large variability of thymic epithelial cells. Algorithms developed in Grün’s laboratory for accurate characterization of differences in the genetic activity of individual cells made it possible to identify cells with potential precursor activity.

In a second step, these predictions were experimentally verified by the researchers using the “barcoding” system developed in Thomas Boehm’s lab using the CRISPR gene scissors. The barcoding process makes it possible to provide progenitor cells with a molecular signature that is transmitted by all cells that emerge from the progenitor. This makes it possible to derive a family tree of epithelial cells.

Anja Nusser of the Boehm lab and Sagar of the Grün lab have developed a method that links information from a family tree to the molecular characteristics of individual cells. This made it possible for the first time to study the development of the thymic epithelium at different ages. This description is of particular interest to immunologists because the thymus undergoes significant changes throughout life. In the early stages of development, there is rapid organ growth and associated massive T-cell production, while in aging there is a gradual loss of functional epithelial cells in the thymus and consequently decreased T-cell production. Age-related loss of function is associated with a weakened immune system.

The arrangement of progenitor cells determines the composition of thymic tissue

In their analysis, the researchers were able to identify two groups of bipotent precursors of the thymic epithelium. The ‘early’ ancestral population assumes the major role in thymic formation during the embryonic stage and in the adolescent organism, while the later ‘postnatal’ ancestral population largely determines further thymic formation in adulthood. The composition of the thymic epithelium is modulated differently by the chronology of the progenitor population.

At early time points, thymic cortical epithelial cells are formed, which mainly contribute to the production of T cells, while at later time points, the main production is on medullary epithelial cells, which ensures that self-reactive T cells are not released from the thymus into the body and thus Make an important contribution to autoimmune protection.

New ways to increase thymus function

The skillful combination of genetically modified animal models from the Boehm laboratory with the latest methods for single-cell characterization in the Grün working group allowed researchers to study the effect of the epithelial cell proliferation method, which had been known for years, on the thymus. It was of great interest to determine whether early stimulation of the thymus with a special growth factor leads to undesirably faster consumption of stem cells and consequently to premature shrinkage of the thymus.

The team’s data suggests that’s not the case. “The thymus we stimulated in an old mouse is still larger than that in a young unstimulated mouse. The structure of the stimulated thymus tissue also demonstrates the normal structure of cortical areas and medulla regions within the organ,” says Max Planck Director Thomas Bohm. With these findings, the Freiburg researchers laid the foundation for the development of new therapeutic approaches to treat age-related thymic shrinkage and treat T-cell-dependent autoimmune diseases.

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