Susceptibility to infections: boost the immune system (again).

A new impetus to thymus aging
Susceptibility to infections: boost the immune system (again).



by Gunnar Bartsch *

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The efficiency of the immune system declines with age, and the elderly are more prone to infections. Research teams from Würzburg and Freiburg have now discovered an approach that can be used to slow this process down.

The thymus, a small lymphatic organ, lies behind the breastbone. It shrinks significantly with age, which weakens the immune system.

(Photo: CLIPAREA.com – stock.adobe.com)

The coronation pandemic made it clear: older people are more prone to infections, infectious diseases are more severe for them than young people, and it takes much longer for them to recover. In fact, the performance of the human immune system has been steadily declining since the age of around 60.

The reason for this is well known: ‘So-called T cells play a key role in foreign body detection and defense against infection,’ explains Professor Dominic Grün, Department of Computational Biology of Spatial Biomedical Systems at Julius Maximilian University. Würzburg (JMU) and director of the Institute of Systems Immunology.

T cells are part of the adaptive immune system. They mainly develop in the early years of life in the thymus gland, a small lymphoid organ located in the chest behind the breastbone. “However, the thymus shrinks with age and allows fewer and fewer T cells to mature, resulting in a weakened immune system,” said Professor Thomas Boehm, head of the working group at the Institute of Immunobiology and Epigenetics. Max Planck.

What happens when the thymus gland shrinks?

Grün and Boehm have now decoded new details of the processes that occur during thymus contraction together. Their findings, which scientists have presented in this issue of the journal Nature, could at least help slow down age-related decline in immune function and develop new therapies to reduce these age-related risks.

They have already done important preparatory work in this direction over the past decades. Thomas Boehm’s working group was able to identify the genetic switches required in the thymus for T-cell maturation. thymic epithelial cells, which attract T cell precursors and lead them to mature. Earlier work in Boehm’s laboratory showed that the two main forms of thymic epithelium arise from bipotent progenitor cells. So far, however, it has not been clear whether there is more than one precursor type and how many subtypes the precursors vary.

The tissue structure of a stimulated thymic organ does not differ from that of an unstimulated organ.  As a sign of a well-functioning thymus, the marginal (red) and inner (green) areas are sharply separated from each other.
The tissue structure of a stimulated thymic organ does not differ from that of an unstimulated organ. As a sign of a well-functioning thymus, the marginal (red) and inner (green) areas are sharply separated from each other.

(Photo: MPI for Immunobiology and Epigenetics, Boehm)

“To better understand why the thymus contracts over the course of life, it is necessary to know exactly what cell types are in it,” explains Dominic Grün. It would be of particular scientific interest if so-called “naive progenitor cells” could be detected in the tissue. These progenitor cells can mature into all types of thymic epithelial cells and therefore constitute an important starting point for counteracting the decline in thymic function.

Single cell biology – every cell at a glance

In fact, two working groups were now able to detect such progenitor cells in the thymus of adult mice. The most modern methods of single cell biology were used – in particular, the so-called single cell mRNA sequencing. Grün is one of the pioneers in this field and has developed personalized bioinformatics methods in recent years to derive biological knowledge from these complex data.

“This technique makes it possible to create a molecular fingerprint of each cell based on the expression of its genes. Using the molecular fingerprint of each cell, a map of all differentiation pathways can be obtained that reflects the relationship between the cells and thus their family tree, ‘explains Grün.

Using the CRISPR scissors and the transgenic mouse ‘barcoding’ model developed at the Boehm lab, the teams also managed to label all epithelial cells in the growing thymus with molecular ‘barcodes’. Since these individual characteristics were passed on unchanged to all daughter cells throughout their lifetime, scientists were able to decipher relationships between daughter cells at different points in time.

A 'map' of the types of cells in the thymus created by sequencing of single-cell mRNA allows for the differentiation of cell types and the derivation of their differentiation pathways.  (Photo: x)
A ‘map’ of the types of cells in the thymus created by sequencing of single-cell mRNA allows for the differentiation of cell types and the derivation of their differentiation pathways. (Photo: x)

(Photo: University of Würzburg / AG Grün)

The combination of single-cell and barcode sequencing developed at Labor Grün finally made it possible to measure the molecular identity of cells and their relationships at the same time. Using this approach, scientists were able to discover two types of progenitor cells – a population that is active mainly during embryonic development and early life, and a resulting “postnatal” population with increased activity in adulthood.

Target for new therapies

“In this way, we discovered different populations of progenitor cells in the embryonic and adult thymus that can differentiate into different types of mature thymic epithelial cells,” says Grün, describing the main result of a recently published study. These progenitor cells are essential for maintaining tissue function and supporting the development of T cells from the adaptive immune system.

To continue the fight against persistent viruses, memory B cells need the support of other immune cells.

By combining transgenic animal models from Boehm’s laboratory with the single-cell methodology of the Grün group, it was also possible to understand the influence of the long-known method of proliferation of thymic epithelial cells. Scientists have been able to show that a certain growth factor also maintains the progenitor population in the aging thymus and thus counteracts the age-related contraction of this organ. These findings could form the basis for the development of novel therapies that help maintain immune system function in old age.

Original publication: Anja Nusser, Sagar, Jeremy B. Swann, Brigitte Krauth, Dagmar Diekhoff, Lesly Calderon, Christiane Happe, Dominic Grün, and Thomas Boehm: Developmental dynamics of two bipotent types of thymic epithelial ancestors. Nature, DOI: 10.1038 / s41586-022-04752-8. https://www.nature.com/articles/s41586-022-04752-8 (xx)

* G. Bartsch, Julius Maximilian University Würzburg, 97070 Würzburg

(ID: 48393170)

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