An important mechanism that controls immune reactions against microorganisms in the intestine has been detailed by Universitätsmedizin Berlin researchers. The findings of the international study may contribute to the development of new therapies for chronic inflammatory bowel disease.

“We have identified a molecule, c-Maf, which is critical for the development and function of specific regulatory T cells in the gut,"

explains study leader Prof. Dr. Alexander Scheffold of Kiel University. C-Maf prevents the immune system from attacking the microbiota.

Host–microbiota Homeostasis

The immune system protects against the spread of pathogenic germs in the intestine. At the same time, it allows the colonisation of beneficial microorganisms.

Conversely, the composition of the microorganisms in the intestine, the microbiota, has an influence on the quality of the immune reaction. This research uncovered a critical mechanism that establishes the homeostasis (balance) between immune system and microbiota.

The team focused on so-called regulatory T cells. These are immune cells that prevent harmless or even useful microorganisms in the intestine from being attacked by the immune system.

“If this molecule is missing, the gut’s immune system overreacts and the microbiota composition changes considerably,"

said first author Dr. Neumann of Charité’s Institute of Microbiology, Infectious Diseases and Immunology.

Excessive Signaling

This change in composition proved remarkably stable: When the researchers transferred the altered microbiota to mice with intact c-Maf-dependent regulatory T cells, they also developed an overreaction of the intestinal immune system.

“These results show that both the immune system and the microbiota mutually contribute to establishing and maintaining the balance in the gut,” says Prof. Scheffold. “This could explain how a microbial imbalance can contribute to chronic inflammatory bowel disease and why the treatment often fails."

These findings could lead to new therapeutic approaches that, in the case of inflammatory bowel disease, aim to influence and harmonize both immune response and microbiota. In the future, the team would like to study how an established pathological interaction between intestinal bacteria and the immune system can be destabilized in patients and restored to its original state.

The work was supported by the Deutsche Forschungsgemeinschaft, the German Federal Ministry of Education and Science, the ‘European Regional Development Fund’ ERDF 2014-2020, Deutsches Rheuma-Forschungszentrum, the Helmholtz Association, the National Health and Medical Research Council, the Sylvia and Charles Viertel Foundation, a Walter and Eliza Institute Centenary Fellowship, and the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC Independent Research Institute Infrastructure Support scheme.

Christian Neumann, Jonas Blume, Urmi Roy, Peggy P. Teh, Ajithkumar Vasanthakumar, Alexander Beller, Yang Liao, Frederik Heinrich, Teresita L. Arenzana, Jason A. Hackney, Celine Eidenschenk, Eric J. C. Gálvez, Christina Stehle, Gitta A. Heinz, Patrick Maschmeyer, Tom Sidwell, Yifang Hu, Derk Amsen, Chiara Romagnani, Hyun-Dong Chang, Andrey Kruglov, Mir-Farzin Mashreghi, Wei Shi, Till Strowig, Sascha Rutz, Axel Kallies & Alexander Scheffold c-Maf-dependent Treg cell control of intestinal TH17 cells and IgA establishes host–microbiota homeostasis Nature Immunology (2019) DOI-

_Image: CDC/Gilda L. Jones _

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