As recently as a few decades ago, the following response was feared: following an organ transplant, the patient’s immune system recognizes the transplanted organ as “foreign” and therefore attacks and rejects it. It was not until the discovery, nearly 30 years ago, that the mycotoxin cyclosporin A can prevent the rejection of a transplanted organ that this response lost its capacity to terrify.
“In T cells, which are important cells in the immune system, cyclosporin A inhibits the activation of a group of transcription factors called NFAT factors,” explains Professor Edgar Serfling, a researcher at the University of Würzburg’s Institute of Pathology. At the time, this finding was tantamount to a “revolution in transplantation medicine”. “Thousands of patients owe their lives to cyclosporin A and the inhibition of NFAT factors,” says Serfling.
Now Serfling, his Research Associate Amiya K. Patra, and other scientists at the University of Würzburg have uncovered new details of the interaction between transcription factors and immune cells. Their work has just been published online in the journal Nature Immunology.
The development of T cells
To enable T cells to recognize transplanted organs or pathogenic viruses and bacteria as foreign material, they first have to be “educated”. This education takes place in the thymus – hence the name T cells. There, the immigrant progenitor cells of the cells later known as thymocytes are subjected to various selection processes in which NFAT factors also play an important role. “If errors occur in these processes, this often leads to autoimmune diseases, such as multiple sclerosis, psoriasis, and rheumatism,” explains Serfling. In multiple sclerosis, for example, autoreactive T cells in the brain attack the myelin sheaths of nerve cells, causing the fatal symptoms of this disease.
In the thymus, thymocyte progenitors develop special receptors on their surface where the body’s own transmitter interleukin 7 (IL-7) can dock. After it has docked, IL-7 transmits signals that activate or deactivate numerous genes in the cells. The progenitor cells subsequently divide and evolve into mature thymocytes.
New insights into the development process
As Amiya Patra has now revealed, NFAT factors also play a significant part in these processes: “If a specific NFAT factor is deactivated in mice, the thymocytes remain in their earliest stage of development and no thymus is created,” explains Serfling. However, if the early steps of thymocyte development that are controlled by IL-7 proceed without disruption, the cell soon forms other receptors that are important to its development and the IL-7 receptor disappears.
Though it is not just the absence of the NFAT factor that disrupts cell development; an excess also messes up the process: the development of thymocytes stops, but at a later stage in this case, and again with fatal consequences: “Specific progenitor receptors are created in an uncontrolled manner, with the result that the person affected develops leukemia, and NFAT factors play a critical role in this too,” explains Serfling.
Approach for new therapies
Through their work the Würzburg team has demonstrated that NFAT factors are critically involved not only in the recognition of the body’s own tissue and in immune responses, but also in the “education” of T cells in the thymus. They therefore represent a target structure that will play a key role in therapies for autoimmune diseases and leukemia in the future.
“An alternative NFAT-activation pathway mediated by IL-7 is critical for early thymocyte development”. Amiya K Patra, Andris Avots, René P Zahedi, Thomas Schüler, Albert Sickmann, Ursula Bommhardt & Edgar Serfling; Nature Immunology, doi:10.1038/ni.2507
Prof. Dr. Edgar Serfling, T: +49 (0)931 31-81207,
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