Is the immune system intelligent

Intelligent building blocks: structural cells in the body control the immune function

research results

The human body is made up of highly specialized components. Bones and soft tissue provide the form, organs take care of blood circulation, digestion and other functions, and immune cells fight pathogens. In fact, many cell types and organs have more than one role to play. Scientists at CeMM describe an impressive example of the “multitasking” of cells. In their current study, they analyzed the epigenetic and transcriptional regulation in structural cells (i.e. in epithelial cells, endothelial cells and fibroblasts) - the most important structural components of our body.

The researchers were able to demonstrate a surprisingly diverse activity of immune genes, although these structural cells are actually not cells of the immune system. Structural cells are not only the building blocks of the body, they are also closely integrated into the immune system. The results of the study, which was published in the renowned journal Nature, underline the importance of a neglected part of the immune system and open up exciting perspectives for research and future therapies.

Our immune system protects us from constant attacks by viruses, bacteria and other pathogens. Much of this protection is provided by hematopoietic (i.e. blood-based) immune cells that specialize in fighting pathogens. These include macrophages, which remove pathogens; T cells that kill virus infected cells; and B cells, which produce neutralizing antibodies against pathogens. However, the body's own defense functions are not limited to these specialists. Many other cell types can recognize infections and contribute directly or indirectly to the immune response against pathogens.

Structural cells are the central building blocks of the body and play an important role in the construction and structure of tissues and organs. Epithelial cells form the surface of the skin and they separate tissues and organs from one another; Endothelial cells cover the inside of the blood vessels; and fibroblasts produce connective tissue that shapes and holds organs together. Despite their well-researched role in autoimmune diseases (e.g. rheumatoid arthritis, inflammatory bowel disease) and cancer, structural cells have a reputation for being simple and uninteresting parts of the body. In their new study, Thomas Krausgruber, Nikolaus Fortelny and colleagues in Christoph Bock's laboratory at CeMM dedicated themselves to researching structural cells and their immune regulation. To do this, they carried out a systematic, genome-wide analysis of the epigenetic and transcriptional regulation of these structural cells.

For this purpose, the research group created a comprehensive catalog of gene activity and gene regulation in three types of structural cells (epithelial cells, endothelial cells and fibroblasts), isolated from 12 different organs of healthy mice. Several technologies were used for high-throughput sequencing (RNA-seq, ATAC-seq, ChIPmentation). These data show that central immune genes are active in structural cells and exhibit complex cell-type and organ-specific gene regulation. In-depth bioinformatic analysis has also identified a network of interactions between structural cells and hematopoietic immune cells. This gives concrete indications of the biological mechanisms with which structural cells contribute to the defense against disease.

Interestingly, many immune genes showed special epigenetic properties that are normally associated with high gene expression, while the expression observed in structural cells of healthy mice was rather low. The CeMM researchers therefore hypothesized that these genes are epigenetically preprogrammed for rapid activation when they are needed - for example in response to a pathogen. To test this theory, they cooperated with Andreas Bergthaler and his laboratory at CeMM and studied the immune response to viral infections.

The mice were infected with a virus (LCMV) that elicited a broad immune response, whereupon many of the epigenetic preprogrammed genes were actually upregulated. In doing so, these genes contributed to the changes that structural cells show in response to a viral infection. These results suggest that structural cells have an “epigenetic potential” that enables rapid immune responses. As an additional validation, the researchers triggered an artificial immune response by injecting mice with cytokines and found that many of the same genes were activated.

The new study reveals a remarkable complexity in the regulation of immune genes in the body's structural cells. The results underline that structural cells are not only the central building blocks of our body, but also make a significant contribution to the defense against pathogens. In the long term, these findings could help develop innovative therapies for diseases that involve the immune system.

The study “Structural cells are key regulators of organ-specific immune responses” was published on July 1, 2020 in Nature. DOI: 10.1038 / s41586-020-2424-4

Thomas Krausgruber *, Nikolaus Fortelny *, Victoria Gernedl, Martin Senekowitsch, Linda C. Schuster, Alexander Lercher, Amelie Nemc, Christian Schmidl, André F. Rendeiro, Andreas Bergthaler and Christoph Bock | * shared first authorship

The study was carried out with the support of a New Frontiers Group Award from the Austrian Academy of Sciences, grants from two special research areas of the Austrian Science Fund (FWF SFB F 6102-B21; FWF SFB F 7001-B30) and research funding from the European Research Council (ERC) as part of the research and innovation program “Horizon 2020” financed by the European Union (grant agreement no. 679146 to Christoph Bock and grant agreement no. 677006 to Andreas Bergthaler). Thomas Krausgruber was supported by a Lise Meitner grant from the Austrian Science Fund (FWF M2403). Nikolaus Fortelny was supported by a grant from the European Organization for Molecular Biology (EMBO ALTF 241-2017). Alexander Lercher was supported by a DOC grant from the Austrian Academy of Sciences.

Christoph Bock has been a Principal Investigator at CeMM since 2012. He conducts interdisciplinary research to understand the epigenetic and gene regulatory basis of cancer and to advance precision medicine with genomics technologies. His research group combines experimental biology (high-throughput sequencing, epigenetics, CRISPR screening, synthetic biology) with computer science (bioinformatics, machine learning, artificial intelligence). He is also visiting professor at the Medical University of Vienna, scientific coordinator of the Biomedical Sequencing Facility (BSF) at CeMM, and key researcher at the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases. He coordinates an EU project Horizon 2020 for the single cell analysis of human organoids as a contribution to the human cell atlas. Christoph Bock is an elected member of the Young Academy of the Austrian Academy of Sciences and has received significant research awards, including the Otto Hahn Medal from the Max Planck Society (2009), an ERC Starting Grant (2016-2021) and the Overton Prize from the International Society of Computational Biology (2017).

The CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences is an international, independent and interdisciplinary research facility for molecular medicine under the scientific direction of Giulio Superti-Furga. The CeMM is based on medical requirements and integrates basic research and clinical expertise in order to develop innovative diagnostic and therapeutic approaches for precision medicine. The main research areas are cancer, inflammation, metabolic and immune disorders as well as rare diseases. The institute's research building is located on the campus of the Medical University and the Vienna General Hospital.

Scientific contact:
Christoph Bock
[email protected]
Original publication:
The study “Structural cells are key regulators of organ-specific immune responses” was published on July 1, 2020 in Nature. DOI: 10.1038 / s41586-020-2424-4
Additional Information: