Lipids launch lethal payload

The defensive artillery of our immune system — that is one way to describe natural killer (NK) cells and T-cells. Both contain cytotoxic granules; packages carrying a lethal payload with which they can neutralise external pathogens such as viruses, as well as internal threats such as tumour cells. Directing these killers requires extraordinary precision: after all, they must only strike their intended target and leave healthy body cells unharmed. Yet exactly how this system functions has not been fully elucidated.

In Science Immunology, a team of researchers from Austrian and German institutes and hospitals now presents new insights, revealing that various lipids play a role in launching the toxic payload. Using CRISPR-based genetic screening, they unexpectedly identified several genes that form part of cellular lipid metabolism, but which also play a key role in the release of cytotoxic granules. Specific lipids ensure that the correct proteins reach the correct location within the killer cells, so that the release of the payload also strikes the right target.

This role of lipids is not only important for a better understanding of how our immune system works, but also sheds new light on various genetic disorders, including several rare neurological conditions and hereditary immune diseases. ‘By following genetic pathways in a highly systematic manner and combining that with functional genomics and mechanistic studies, we have uncovered a new group of genes that determine the functioning of NK and T-cells,’ says co-author Artem Kalinichenko (MedUni Graz).

A. Kalinichenko, J. Heumer, et al., Protein palmitoylation and sphingolipid metabolism control regulated exocytosis in cytotoxic lymphocytes, Science Immunology (2025), doi:10.1126/sciimmunol.ado3825