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Researchers Elucidate Transport Pathway of Immune System Substances

  To transport substances from the site of their production to their destination, the body needs a sophisticated transport and sorting system. Various receptors in and on the 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. Studies by Stefanie Herda and Dr. Armin Rehm (Max Delbrück Center for Molecular Medicine, MDC, Berlin-Buch and Charité–Universitätsmedizin 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)*.

In the
search for diseases, the 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.

is produced by cytotoxic T cells (formerly: T killer cells), T helper cells and
natural killer cells. It enhances the activity of immune cells and induces
other cells of the body to increasingly present fragments of the pathogen on
their surface so that the T cells can find the 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 these packages and navigate them to their
destination. Without Sortilin, however, the packages cannot be delivered and
remain in the post office, that is in the Golgi apparatus. Correspondingly, in
the serum, i.e. outside of the cell, too little interferon-gamma is present. Thus,
lack of interferon-gamma is not caused by diminished production, but rather by
reduced or abrogated transport activity, eventually preventing the
interferon-gamma from reaching its destination. This in turn leads to a
weakened immune defense system since the 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, this molecule ensures that transport packages
containing granzyme A as part of its cargo reach their correct address in the
cell. The work of the researchers led by Dr. Rehm suggests that Sortilin has an
indirect influence on VAMP7 by promoting transport routes that lead to the
degradation of 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.

Sortilin influences two different transport pathways for key immunological effector
molecules in an opposite manner. Without Sortilin, less interferon-gamma is
available, instead there is an increased level of granzyme A. But the increased
concentration of granzyme A cannot compensate for the interferon gamma
deficiency. In the experiment, the immune system of mice in which the
researchers had deactivated Sortilin was significantly weaker and the fight
against viruses and bacteria was less effective. The advantage for these
animals, however, was that autoimmune diseases – that is, diseases in which
one’s own immune system reacts against the 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

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

Max-Delbrück-Center for Molecular Medicine (MDC); Department of Hematology, Oncology
and Tumorimmunology, 13125 Berlin, Germany

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

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

Max-Delbrück-Center for Molecular Medicine (MDC); Department of Tumor- and Immunogenetics,
13125 Berlin, Germany


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