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Trans-presentation – a fundamental new principle for immunoregulation

08.12.2016

Kiel biochemists from the Cluster of Excellence "Inflammation at Interfaces" describe a new mechanism for the activation of T cells, in a collaborative project with the universities of Mainz and Munich.

Interleukin 6 (IL-6) is a central signalling substance of the immune system and involved in many inflammatory processes. As such, the protein's functions can be very different, depending on how it activates cells. On the one hand, IL-6 helps with the regeneration of tissue, and is indispensable for combating bacterial infections (classical signalling). On the other hand, it also stimulates chronic inflammations, such as in the case of rheumatoid arthritis or chronic inflammatory bowel diseases (trans-signalling). The role of the chemical messenger in autoimmune processes, which are related to multiple sclerosis, has been investigated in a recent study led by Professor Thomas Korn (Munich) and Professor Ari Waisman (Mainz). The study identified that the messenger also uses a third method for transmitting its signals. This mechanism, which has been named “trans-presentation”, has been clarified by the Kiel biochemists Professor Stefan Rose-John and Dr. Christoph Garbers, from the Cluster of Excellence “Inflammation at Interfaces”, in cooperation with the working groups from Munich and Mainz. The results have already been published online in Nature Immunology. Rose-John is convinced that this work is significant in relation to treatment with Interleukin 6 inhibitors.

Chemical messengers such as Interleukin 6 (IL-6) or tumour necrosis factor-alpha (TNFα) are the focus of research on illnesses related to chronic inflammations and dysfunctions of the immune reaction. These messengers influence many processes in the immune system, and are the target structures for new, biotech-developed medications, so-called “biologicals”. Some of them have already been used to combat illnesses such as rheumatism, psoriasis or chronic inflammatory bowel diseases. In order to gauge the effects and side-effects of these kinds of treatments, it is important to fully understand the biology of messenger substances. The Institute of Biochemistry at Kiel University is one of the leaders in Interleukin 6 biology. “What distinguishes my working group, and what makes us highly valuable partners for many laboratories worldwide, is that we have the best tools available to research IL-6 signalling”, said Cluster board member Professor Stefan Rose-John.

In the paper published in Nature Immunology, the focus was on immunological processes in connection with Interleukin 6 signals, which are associated with the disease pattern of multiple sclerosis (MS). MS is an inflammatory disease of the central nervous system, in which immune cells attack the protective (myelin) sheath surrounding nerve cells. In order to trigger the animal model for MS, experimental autoimmune encephalomyelitis (EAE), the animals must, amongst other things, be able to produce IL-6. Rose-John said: “It has been known for a long time that IL-6 knock-out mice do not develop EAE.” However, pathogenic immune cells which attack the myelin sheath are not always produced when IL-6 is secreted. According to the study, the decisive factor is that a specific cell type, the so-called “dendritic cells”, are able to synthesise IL-6 and the IL-6 receptor. These cells are responsible for detecting foreign substances (antigens), presenting T cells, and thereby triggering a specific immune response. If the dendritic cells simultaneously secrete IL-6, a kind of molecular switch is flipped in the T cells. They then become pathogenic, developing properties which severely damage tissue.
The specific circumstances required for this to take place have been identified by Rose-John and his colleague Dr. Christoph Garbers. They discovered an as yet unknown principle of signal transmission: trans-presentation. Dendritic cells present IL-6 which is bound to the IL-6 receptor to T cells. Through this cell-to-cell interaction, there is massive T cell stimulation, which is required for the development of EAE.

Previously, two signal paths were known: firstly, via membrane-bound Interleukin-6 receptors, and secondly via soluble receptors. The membrane-bound forms of the receptor are only found in very few cells in the human body. Through ‘classical signalling’ in particular, the regenerative properties of IL-6 are activated. In contrast, the soluble forms of the receptor can activate practically all cells in the body via ‘trans-signalling’. “It is assumed that this signalling path, in particular, is responsible for triggering the inflammation-boosting activities of IL-6,” said Dr. Christoph Garbers.

A further discovery made during the study is that trans-presentation may be blocked with inhibitors of IL-6 and IL-6 receptors, but not with sgp130Fc, a potent inhibitor of IL-6 trans-signalling. The sgp130Fc protein was developed at the Institute of Biochemistry at Kiel University, under the leadership of Stefan Rose-John, and is currently being clinically tested as a therapy for people with chronic inflammatory bowel diseases. Rose-John said: “We don't know exactly which immunological processes this kind of trans-presentation plays a role in. Only when this is clear, we judge whether it's good or bad that we cannot inhibit this with soluble gp130Fc. It is possible that trans-presentation of IL-6 plays a decisive role in anti-viral processes. This trans-presentation would be blocked by treatments which inhibit all IL-6 signal paths, but not by the gp130Fc protein, which only inhibits IL-6 trans-signalling. Blocking IL-6 entirely causes patients to experience a higher incidence of infectious diseases. This shows that much more research must be done on this topic.”

Original publication:
Heink S et al.: Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic TH17 cells. Nature Immunology (2016), published online November 28, 2016
doi:10.1038/ni.3632.

Stefan Rose-John, Cluster of Excellence "Inflammation at Interfaces" and Institute of Biochemistry at Kiel University. Photo: Dr. Tebke Böschen/ Kiel University

 

Contact:
Prof. Dr. Stefan Rose-John
Kiel University
Institute of Biochemistry
Tel.: 0431/880-3336


Cluster of Excellence "Inflammation at Interfaces"
Scientific Office, Head: Dr. habil. Susanne Holstein
Press and Communications, Sonja Petermann, Text: Kerstin Nees
Postal address: Christian-Albrechts-Platz 4, 24118 Kiel, Germany
Tel.: +49 (0)431 880-4850, Fax: +49 (0)431 880-4894
E-mail:
Website: www.inflammation-at-interfaces.de


The Cluster of Excellence "Inflammation at Interfaces" has been funded since 2007 by the Excellence Initiative of the German Government and the federal states with a total budget of 68 million Euros. It is currently in its second phase of funding. Around 300 cluster members are spread across the four locations: Kiel (Kiel University, University Medical Center Schleswig-Holstein (UKSH)), Lübeck (University of Lübeck, UKSH), Plön (Max Planck Institute for Evolutionary Biology) and Borstel (Research Center Borstel (FZB) – Center for Medicine and Biosciences) and are researching an innovative, systematic approach to the phenomenon of inflammation, which can affect all barrier organs such as the intestines, lungs and skin.

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