Immune cells in the starting blocks: ’Always ready’ is hard work

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(© Image: Adobestock)
(© Image: Adobestock)

When pathogens invade the body, the immune system must react immediately and prevent or contain an infection. But how do our immune cells stay ready when there is no attacker in sight? Scientists from Vienna and Salzburg have come up with an intriguing explanation: They are stimulated by healthy tissue. This means they never come to rest and are immediately ready for action when they are needed. This finding could be used to develop drugs in the future to specifically increase the alertness of our immune system.

Communication is crucial in immune defense: when a virus infects a cell, for example, the cell releases signaling molecules. This alerts defense cells, and our entire immune system is active within a very short time. Immune cells process these signals in particular via the JAK-STAT signaling pathway - named after Janus, the two-headed Roman god of beginnings and endings. This signaling pathway acts like a direct line from signal recognition to the nucleus of the immune cells, where it activates a series of genes and sets the cells into attack mode.

Even if there is no danger at the moment, our immune cells must always be vigilant. At the same time, they must not cause any damage through unnecessary activity, as is the case with autoimmune diseases. How our immune cells maintain this balance is still poorly understood. A team of Viennese research groups ( ) including Salzburg University Professor Nikolaus Fortelny from the Department of Biosciences and Medical Biology at PLUS has now presented an explanation in the renowned journal"Nature Immunology": "The same JAK-STAT signaling pathway that activates the immune cells during an infection also keeps them on standby," explains Christoph Bock, Principal Investigator at CeMM and MedUni Vienna. The immune cells therefore only have to increase the intensity of the signaling pathway during an infection; this is much faster than switching a signaling pathway on again completely.

To come to this conclusion, the team examined twelve different mouse models in each of which one component of the JAK-STAT signaling pathway is genetically altered. These mice were raised free of disease and compared with genetically unaltered mice. It was noticed that these mice partially lacked the characteristic gene activity and epigenetic regulation of the readiness state. Something similar happened when the immune cells were removed from their natural environment and kept in the laboratory: They lost their characteristic state of readiness and in some cases even their identity as defense cells.

The team analyzed the gene expression and epigenetics of immune cells and tissue samples collected by 7 research teams from Vienna. "Our analyses were only possible by establishing uniform laboratory standards and robust statistical methods," explains bioinformatician Nikolaus Fortelny (first author and now professor at the University of Salzburg). "We were able to show that signaling pathways such as JAK-STAT have different functions in a state of readiness than during an immune response," says molecular biologist Matthias Farlik (also first author and now group leader at MedUni Vienna), describing the project.

"JAK-STAT is a central mechanism of our body to communicate immune signals," says Thomas Decker (Professor at the Max Perutz Labs and the University of Vienna), summarizing the relevance of the study. "Our study offers insights into the role of the immune system: not only to react to attacks, but also to maintain vigilance without causing unnecessary damage," adds Mathias Müller (Professor at the Vetmeduni Vienna). Genes of the JAK-STAT signaling pathway are sometimes pathologically altered in people with immune diseases and cancer. This research therefore also provides potential approaches for new therapies.

The study "JAK-STAT signaling maintains homeostasis in T cells and macrophages" was published in the journal Nature Immunology on April 23, 2024.DOI: 10.1038/s41590’024 -01804-1

Authors: Nikolaus Fortelny, Matthias Farlik, Victoria Fife, Anna-Dorothea Gorki, Caroline Lassnig, Barbara Maurer, Katrin Meissl, Marlies Dolezal, Laura Boccuni, Aarathy Ravi Sundar Jose Geetha, Mojoyinola Joanna Akagha, Anzhelika Karjalainen, Stephen Shoebridge, Asma Farhat, Ulrike Mann, Rohit Jain, Shweta Tikoo, Nina Zila, Wolfgang Esser-Skala, Thomas Krausgruber, Katarzyna Sitnik, Thomas Penz, Anastasiya Hladik, Tobias Suske, Sophie Zahalka, Martin Senekowitsch, Daniele Barreca, Florian Halbritter, Sabine Macho-Maschler, Wolfgang Weninger, Heidi A. Neubauer, Richard Moriggl, Sylvia Knapp, Veronika Sexl, Birgit Strobl, Thomas Decker, Mathias Müller, Christoph Bock

This work was funded by the Austrian Science Fund FWF, the European Molecular Biology Organization (EMBO) and the European Research Council (ERC).

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