500 million year reset for the immune system
A single factor has the potential to reset the immune system of mice to a state similar to what it was 500 million years ago, a time when the first vertebrates emerged.
Scientists at the Max Planck Institute of Immunobiology and Epigenetics (MPI-IE) in Freiburg re-activated the expression of an ancient gene, which is not usually expressed in the mammalian immune system, and discovered that these animals developed a fish-like thymus. To the researchers astonishment, while the mammalian thymus is utilised exclusively for T cell maturation, the reset thymus produced not only T cells, but also served as a maturation site for B cells – a property normally seen in the thymus of fish alone. Therefore, the model potentially could provide a new insight of how the immune system had developed in the course of evolution. The study has been published in Cell Reports.
The adaptive immune response is unique to vertebrates. One of its core organs is the thymus, which is present in all vertebrate species. Epithelial cells in the thymus control the maturation of T cells, which later fight degenerated or infected body cells. The gene FOXN1 is in charge of the development of such T cells in the mammalian thymus. Scientists led by Thomas Boehm, director at the MPI-IE and head of the department for developmental immunology, activated the evolutionary ancestor of FOXN1, called FOXN4, in the thymic epithelial cells of mice. FOXN4 is present in all vertebrates, but appears to play only a role in the maturation of immune cells of jawed fish, such as cat sharks and zebra fish.
“The simultanuous expression of FOXN4 and FOXN1 in the mouse led to a thymus that showed properties as in fish,” said first author Jeremy Swann. Coupled with earlier results this implies that the development function of thymic tissue was originally initiated by FOXN4. Due to an evolutionary gene duplication, which led to FOXN1, transiently both genes, and finally only FOXN1 were active in the thymus.
To the surprise of the research team, not only T-cells developed in the thymus of mice, but also B-cells. Mature B-cells are responsible for antibody production. In mammals, they usually do not mature in the thymus, but in other organs, such as the bone marrow.
“Our studies suggest a plausible scenario for the transition of a bipotent lymphopoietic tissue to a lymphoid organ supporting primarily T cell development,” said Boehm. Since B- and T-cell progenitors cannot yet be distinguished, it remains unclear whether the B-cell development is based on the migration of dedicated B-cell precursors to the thymus, or to maturation from a shared T/B progenitor in the thymus itself. Comparative studies often suggest that the origin of a particular evolutionary innovation must have occurred in an extinct species. “Here, the re-creation and functional analysis of presumed ancestral stages could provide essential insights into the course of such developments,” explained Boehm the study approach.
Contributing Source: Max-Planck-Gesellschaft
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