Research reveals how immune cells orchestrate the release of toxic granules

When immune cells strike, precision is everything. New research reveals how natural killer and T cells orchestrate the release of toxic granules – microscopic packages that destroy virus-infected or cancerous cells. The study led by researchers from CeMM, St. Anna CCRI, MedUni Vienna, Med Uni Graz, the University Hospital Bonn (UKB) and the University of Bonn, published in Science Immunology (DOI: 10.1126/sciimmunol.ado3825), uncovers an unexpected link between lipid metabolism and the immune system's ability to deliver its lethal cargo, offering new insights into diseases caused by genetic defects.

Our immune system relies on specialized cells, such as natural killer (NK) cells and T cells, to find and destroy dangerous invaders like viruses or cancer cells. To do this, they release "packages" filled with powerful molecules – so-called cytotoxic granules – that kill infected or cancerous cells. Although some key molecules have been identified through immune disorders and their effects, others that might be important for this release mechanism are still unknown.

In their new study published in the renowned journal Science Immunology (DOI: 10.1126/sciimmunol.ado3825) a team of scientists led by Kaan Boztug, Professor at the Medical University of Vienna, Principal Investigator at the St. Anna Children's Cancer Research Institute, Adjunct Principal Investigator at the CeMM Research Center for Molecular Medicine as well as Director of the Clinic for Pediatric Immunology and Rheumatology at UKB and member of the ImmunoSensation² Cluster of Excellence at the University of Bonn, together with Artem Kalinichenko, Assistant Professor at the Medical University of Graz and former Senior Postdoc at St. Anna CCRI and CeMM as well as Jakob Huemer, former PhD Student at CeMM, (both former members of the research group of Kaan Boztug), has made a discovery that changes the way we understand how our immune system fights disease.

By using a CRISPR-based genetic screening approach, the researchers identified a set of unexpected genes that play a key role for the precise release of cytotoxic granules in human NK and T cells. Surprisingly, many of these genes are connected to cellular lipid metabolism. The team discovered that specific lipids help guide important proteins to the right place inside immune cells, including targeted release of cytotoxic granules and the delivery of their deadly packages to keep the body safe.

This breakthrough not only helps explain how immune cells work but also sheds light on diseases caused by genetic defects, such as certain rare nerve disorders and inherited immune problems. "By systematically exploring genetic pathways and combining functional genomics with mechanistic follow-up, we have uncovered a new group of genes that control how T and NK cells function and kill both virus-infected cells or tumor cells," says co-first author Artem Kalinichenko.

It's fascinating to see how molecules originally known from neuronal biology and associated with lipid metabolism and modification are also key for a distinct immune defense mechanism. Our findings open up new questions about how shared cellular pathways shape very different biological systems."

Jakob Huemer, co-first author of the study

"This work showcases the power of collaborative, curiosity-driven research," concludes senior author Kaan Boztug. "We were able to uncover a completely unexpected connection between lipid biology and immune cell function and thereby link seemingly unrelated biological processes. These findings will further help us improve diagnosis of patients with rare immune defects, and are also relevant for future development of cancer immunotherapy approaches."

The research was carried out in international collaboration with teams from Austria, France, Sweden, and Finland, and represents an important step forward in understanding how our bodies fight infections and cancer.