Communication is crucial to immune defense. When a virus infects a cell, the cell releases signaling molecules called cytokines. Cytokines alert specialized immune cells, and our immune system is rapidly activated. Immune cells process key signals via the JAK-STAT signaling pathway – a pathway named after Janus (JAK), the two-faced Roman god of beginnings and endings. JAKs are protein tyrosine kinases, while STATs (Signal Transducers and Activators of Transcription proteins) regulate gene transcription in the nucleus. JAKs link signals originating at the cell surface to the gene regulatory machinery of immune cells, thereby putting the immune cells into attack mode.
Even when there is no immediate threat, our immune cells must remain vigilant. At the same time, they should not cause damage through excessive activity, which can lead to inflammation and autoimmunity. How our immune cells maintain this balance is poorly understood. The Vienna-based and Austrian Science Fund supported Special Research Program (SFB) in ‘Monarchies and Hierarchies in Shaping Chromatin Landscapes’ investigates the JAK-STAT pathway in immune cell signaling. Perutz PI Thomas Decker emphasizes: “It is fair to say that Vienna probably has the highest density of renowned researchers in the JAK-STAT field worldwide, and they are all part of this consortium.” The SFB, led by Mathias Müller from the Veterinary Medical University of Vienna, commenced in 2016 and is concluding its funding period in 2024, “leaving behind a large amount of data that will serve as a valuable resource for future research in the JAK-STAT field”, Thomas explains.
“The same JAK-STAT signaling pathway that activates immune cells during an infection also keeps them on standby when no pathogens are in sight,” explains Christoph Bock, group leader at CeMM and Professor at the Medical University of Vienna. When encountering a pathogen, the immune cells only need to increase the signaling intensity – ‘revving up their engine’ – which is much faster than turning on a completely new signaling pathway. Thomas adds: “The basic principle is that the JAK-STAT pathway, which is known to transform cells from an inactive to an immunologically active state, is also very important in homeostasis.”
The study is an inter-disciplinary work involving four research institutes. Perutz PI Thomas Decker helped not only to conceptualize the study, but also to contextualize the data within the framework of organs and organisms. According to Thomas, "in the intact organ, both paracrine and intercellular signaling play crucial roles in maintaining the homeostatic transcriptome. When these signals are depleted, significant changes are observed in JAK-STAT signaling." This underscores the pathway's importance in maintaining organ integrity, not only during the immune response, but also in cellular homeostasis. Since genes of the JAK-STAT signaling pathway are frequently found to be altered in individuals with immune diseases and cancer, the findings may provide future avenues for therapeutic intervention.
About the study
DOI: 10.1038/s41590-024-01804-1