Thymus Boost | Max Planck Society

Max Planck researchers identify epithelial stem cells that control the growth of the thymus at different stages of life

Many immune cells, which are of crucial importance for our immune system, develop at the beginning of life and into adolescence in a small organ right next to our heart: the thymus. With age, however, the thymus shrinks and its function and thus the number of powerful immune cells decrease. Max Planck research groups from Freiburg and Würzburg have now identified processes that control the development and composition of thymus tissue over the course of life. They also came across potential therapeutic approaches to remedy age-related thymus shrinkage and for the treatment of autoimmune diseases.

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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 degenerated cells, as well as so-called helper T-cells, which help the body to form antibodies.

Over the past few decades, Thomas Boehm’s research group at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg has been able to identify the genetic switches that are required in the thymus for T cell maturation. So-called thymic epithelial cells, which attract T-cell precursors and bring them to maturation, are essential here. The T-cells learn to distinguish diseased from healthy and foreign cells from their own. With it you can detect and eliminate unwanted structures and prevent autoimmune diseases. Previous work in Thomas Boehm’s laboratory had shown that the two main forms of thymic epithelium arise from bipotent progenitor cells. So far, however, it has been unclear whether there is more than one type of precursor and how many sub-types the precursors differentiate into.

Pedigree analysis identifies progenitor cells of the thymic epithelium

In collaboration with the laboratory of Dominic Grün (formerly the Max Planck Institute of Immunobiology and Epigenetics, now the Max Planck Research Group at the University of Würzburg), a specialist in molecular single-cell analysis, the researchers have now analyzed the astonishingly large heterogeneity of thymic epithelial cells on a molecular level detected. The algorithms developed in Grün’s laboratory for the precise description of differences in the gene activity of individual cells made it possible to identify cells with possible precursor activity.

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

Anja Nusser from the Boehm laboratory and Sagar from the Grün laboratory have also jointly developed a method that links information from the family tree with 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 major changes throughout life. In early stages of development there is rapid organ growth and associated massive T cell production, while in old age there is a gradual loss of functional thymus epithelial cells and therefore reduced T cell production. The age-related loss of function is associated with a reduced immune system.

Order of progenitor cells determines composition of thymic tissue

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Massive enlargement of the stimulated thymus organ even in young mice, which is largely retained in old age.

In their analysis, the researchers were able to identify two bipotent precursor populations of the thymus epithelium. An “early” progenitor population assumes the main role in the formation of the thymus during the embryonic phase and in the adolescent organism, while a subsequent “postnatal” progenitor population largely determines the further thymus formation in adulthood. The composition of the thymus epithelium is modulated differently by the temporal sequence of the progenitor populations.

At early time points, mainly cortical thymic epithelial cells are formed, which mainly contribute to the production of T cells, while at later time points, the main production is on medullary thymic epithelial cells, which ensure that no self-reactive T cells are released from the thymus into the body and thus make an important contribution to protection against autoimmunity.

New approaches to increase thymus function

The skilful combination of transgenic animal models from the Boehm laboratory with the most modern methods of single cell characterization in the Grün working group enabled the researchers to examine the effect of a method for the proliferation of epithelial cells, which has been known for years, on the thymus. It was of particular importance to determine whether early stimulation of the thymus with a special growth factor leads to undesirably faster consumption of the stem cells and thus to early shrinkage of the thymus.

The team’s data suggests that is not the case. “The thymus we stimulated in an old mouse is still larger than that in an unstimulated young mouse. The tissue structure of the stimulated thymus also shows the normal structure of cortical zones and medullary areas inside the organ,” says Max Planck Director Thomas Boehm. With these results, the Freiburg researchers have laid the foundation for developing new therapeutic approaches to remedy age-related thymus shrinkage and treat T-cell-dependent autoimmune diseases.

TB / MR

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