Precision is crucial for immune cells: natural killer (NK) cells and T cells eliminate infected or transformed cells by releasing targeted, highly toxic particles. A new study from the CeMM (Research Center for Molecular Medicine of the Austrian Academy of Sciences), the St. Anna Children’s Cancer Research Institute, the Medical University of Vienna, the Medical University of Graz, the University Hospital Bonn (UKB) and the University of Bonn offers deeper insight into how these so-called cytotoxic granules are released.
In the journal Science Immunology, the international research team led by Prof. Dr. Kaan Boztug (– at MedUni Vienna, St. Anna Children’s Cancer Research, CeMM, and UKB and member of the Cluster of Excellence ImmunoSensation2 at the University of Bonn) reports an unexpected link between lipid metabolism and the ability of the immune system to deliver its “deadly cargo” precisely — shedding new light on diseases caused by genetic defects.
Our immune system depends on specialized cells such as NK cells and T cells to detect and destroy dangerous intruders like viruses or cancer cells. These cells release microscopic “packages” filled with highly toxic molecules — the cytotoxic granules — that kill infected or transformed cells. Although previous research into immune disorders uncovered several key molecules involved in this release mechanism, many important mediators remained unidentified.
Using CRISPR-based gene screening methods, the scientists discovered a surprising set of genes that play a central role in the release of cytotoxic granules in human NK and T cells. Many of these genes were linked to the cellular lipid metabolism. The team showed that specific lipids help transport key proteins to the correct location within immune cells to enable the controlled release of the granules — thereby ensuring the targeted killing of infected or transformed cells.
This breakthrough not only improves our understanding of how immune cells function, but also provides new insights into diseases caused by genetic defects — such as rare neurological disorders or inherited immune deficiencies.
“By systematically investigating genetic signalling pathways and combining functional genomics with mechanistic follow-up, we discovered a new group of genes that govern the function of T and NK cells — and destroy both virus-infected and tumour cells,” says co-first author Artem Kalinichenko.
“It is fascinating to observe that molecules originally known from neurobiology and associated with lipid metabolism and lipid modification also play a decisive role in an immune defence mechanism,” adds co-first author Jakob Huemer.
“This work shows the potential of curiosity-driven collaborative research. We uncovered a completely unexpected connection between lipid biology and immune cell function — linking seemingly independent biological processes. These findings will help improve the diagnosis of patients with rare immune deficiencies and are also relevant for the future development of cancer immunotherapy approaches,” summarises lead author Kaan Boztug.
Publication
Artem Kalinichenko et al.,Protein palmitoylation and sphingolipid metabolism control regulated exocytosis in cytotoxic lymphocytes.Sci. Immunol.10,eado3825(2025).DOI: 10.1126/sciimmunol.ado3825
Contact
Prof. Dr. Kaan Boztug
Clinic for Pediatric Immunology and Rheumatology
University Hospital Bonn
E-Mail: kaan.boztug@ukbonn.de
