Researchers Explain Transport Pathway of Immune System
To transport substances from the site of their production to their destination, the body needs a sophisticated transport and sorting system the golgi apparatus
Various receptors in and on cells recognize certain molecules, pack them and ensure that they are transported to the right place. One of these receptors is Sortilin. It is present in the cells of the nervous system, the liver, and the immune system.*
The work is published in the Cell press family of journals: Immunity.
In the search for diseases, T cells of the immune system go on patrol throughout the body. If they encounter a cell infected by viruses, they bind to it and secrete substances that ensure that the target cell dies. One of these substances is granzyme A, which penetrates the infected cell and induces programmed cell death.
In addition, the immune cells secrete interferon-gamma, which induces the surrounding cells to have a stronger immune response. Interferon-gamma is produced by cytotoxic T cells (formerly known as T killer cells), T helper cells and natural killer cells.
Interferon-gamma enhances the activity of immune cells and induces other cells of the body to place fragments of the pathogen on their surface so that the T cells can find affected cells more easily. To facilitate the transport of interferon-gamma from the interior of the T cell where it is produced to the cell membrane where it can be released, the cell uses its interior processing and transport system, to which the Golgi apparatus belongs.
If one were to imagine the Golgi apparatus
as a post office, Sortilin’s task is to wrap
the interferon-gamma cargo into packages
and send them to their destination.
Without Sortilin, however, the packages
cannot be delivered and remain in the post office
the Golgi apparatus.
At the same time, too little interferon-gamma comes
to exist in the serum outside of the cell.
So lack of interferon-gamma is not caused by
diminished production, but by reduced transport,
eventually preventing interferon-gamma
from reaching its destination.
This in turn leads to a weakened immune
defense system as interferon can only exert
its immune-stimulating effect when it is
released from the immune cells.
While the transport of interferon-gamma is disturbed in the absence of Sortilin, the transport of granzyme A which destroys diseased cells directly is more effective.
Granzyme A uses another transport pathway, which is dependent on a multi-part receptor complex. This complex includes the molecule VAMP7. Together with its binding partners, VAMP7 ensures that transport packages containing granzyme A reach their correct address in the cell.
The work by Dr. Rehm's group suggests that Sortilin also has an indirect influence on VAMP7. In cells lacking Sortilin the researchers were able to detect increased VAMP7. This condition allowed for a more efficient transport and therefore an increased release of granzyme A.
But the increased concentration of granzyme A cannot compensate for the interferon gamma deficiency.
In an experiment in which researchers deactivated Sortilin in mice, their immune system was significantly weaker and the fight against viruses and bacteria was less effective. A slight advantage for these animals, however, was that autoimmune diseases in which one’s own immune system reacts against one's own body were much less pronounced.
*The sorting receptor Sortilin exhibits a dual function in exocytic trafficking of interferon-γ and granzyme A in T cells
* Studies by Stefanie Herda and Dr. Armin Rehm (Max Delbrück Center for Molecular Medicine, MDC, Berlin-Buch and CharitéUniversitätsmedizin Berlin) and the immunologist Dr. Uta Höpken (MDC) have now shown that the receptor Sortilin plays an important role in the function of the immune system (Immunity, doi: 10.1016/j.immuni.2012.07.012)*.
Stefanie Herda1, Friederike Raczkowski2, Hans-Willi Mittrücker2, Gerald Willimsky3, Kerstin Gerlach1, Anja A. Kühl4, Tilman Breiderhoff5, Thomas E. Willnow5, Bernd Dörken1,6, Uta E. Höpken7, Armin Rehm1,6
1 Max-Delbrück-Center for Molecular Medicine (MDC); Department of Hematology, Oncology and Tumorimmunology, 13125 Berlin, Germany
2 Institute for Immunology, University Medical Center, 20246 Hamburg-Eppendorf, Germany
3 Charité- Universitätsmedizin Berlin, Institute of Immunology, 12200 Berlin, Germany
4 Charité- Universitätsmedizin Berlin, Department of Pathology/Research Center Immuno Sciences, 12200 Berlin, Germany
5 Max-Delbrück-Center for Molecular Medicine (MDC); Department of Molecular Cardiovascular Research, 13125 Berlin, Germany
6 Charité- Universitätsmedizin Berlin, Department of Hematology, Oncology and Tumorimmunology, 13353 Berlin, Germany
7 Max-Delbrück-Center for Molecular Medicine (MDC); Department of Tumor- and Immunogenetics, 13125 Berlin, Germany
Original article: http://www.mdc-berlin.de/en/news/2012/20121017-researchers_elucidate_transport_pathway_of/index.html