When pathogens invade the body, the immune system must react immediately to prevent or contain an infection. However, it is not fully understood how our defense cells stay vigilant when there are no pathogens in sight. Now, researchers from CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences have discovered these cells are constantly stimulated by healthy tissue to keep them prime and ready to respond to pathogens. Their study in mice suggests future medications could be devised to selectively enhance our immune system’s attention.

The findings are published in Nature Immunology in an article titled, “JAK-STAT signaling maintains homeostasis in T cells and macrophages.”

When a virus infects a cell, the cell releases signaling molecules. Immune cells process such signals through the JAK-STAT signaling pathway, which links signal detection on the cell surface to the core regulatory machinery of immune cells, activating a set of genes and putting the immune cells into attack mode.

“The same JAK-STAT signaling pathway that activates immune cells during an infection also keeps them on standby when no pathogens are in sight,” explained Christoph Bock, principal investigator at CeMM and professor at the Medical University of Vienna.

When encountering a pathogen, the immune cells thus only need to increase the signaling intensity, which is much faster than turning on a completely new signaling pathway.

The researchers examined twelve mutant mouse models, each with a genetically altered component of the JAK-STAT signaling pathway. These mice were raised free of diseases and compared with genetically unaltered mice. It was observed that the mutant mice lacked some of the characteristic gene activity and epigenetic regulation of the standby state. Something similar happened when defense cells were removed from their tissue environment and kept in cell culture: They lost their characteristic standby state and even parts of their identity as immune cells.

The researchers analyzed the gene expression and epigenetics of immune cells and tissue samples collected by seven research teams from Vienna. “Our analyses were only possible due to the establishment of uniform laboratory standards and robust statistical methods,” said bioinformatician Nikolaus Fortelny, first author and now professor at the University of Salzburg. “We showed that JAK-STAT signaling has different functions when immune cells are on standby than during the active response to pathogens,” explained Matthias Farlik, PhD, first author and now group leader at the Medical University of Vienna.

“JAK-STAT signaling is a central mechanism of our body for communicating immune signals,” summarized Thomas Decker, PhD, professor at the Max Perutz Labs and the University of Vienna.

“Our study provides insights into the role of the immune system: not only does it react to attacks, but it also maintains vigilance without causing unnecessary damage,” concluded Mathias Müller, PhD, professor at the University of Veterinary Medicine Vienna.

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