How do immune cells strike a balance, unleashing rapid attacks against pathogens or cancer, while avoiding damage to healthy cells? Research into an immune kill switch holds potential for controlling infections or preventing autoimmunity.
Immune cells called T cells keep us safe, identifying and fighting infections and cancer. These cells need to be activated extremely quickly so they can switch on the right genes to start producing cytokines, the chemical artillery they use to fight the threat.
This response requires finely-tuned control of messenger (m)RNA transcripts, the genetic instructions that cells use to make proteins, including cytokines.
Professor Jernej Ule, runs a lab across the UK Dementia Research Institute at King's College London and the Crick, studying how cells regulate the number of mRNA transcripts and what happens when this tightly controlled system is disrupted.
Our immune system has to strike a very fine balance: too little activation and disease takes over, or we can develop cancer; too much activation and it starts attacking the body, in what's known as autoimmunity
Professor Jernej Ule, Van Geest Professor of Neurodegeneration at King's
In a new study published in Nature Communications, Professor Jernej Ule, Van Geest Professor of Neurodegeneration at King's, joined forces with molecular biologist Professor Randall Johnson and his team at the University of Cambridge to investigate an 'immune kill switch': how T cells switch off immune functions as quickly as they are switched on.
The project expanded into an international effort, as co-first authors Dr Iosifina Foskolou (Cambridge) and Dr Paulo Gameiro (Crick) continued the work, leading teams in their new organisations, Sanquin in Amsterdam and the NOVA University in Lisbon.
Two signals are stronger than one
A rapid shutdown or kill switch means controlling how long mRNAs persist in the cell. Many mRNAs in T cells, including those for cytokines, have more than one shutdown signal. The first is 'AU-rich elements': long stretches of nucleotides (genetic building blocks) that signal to proteins to degrade the mRNA. Another modification, called m6a methylation, adds chemical 'red flags' to mRNAs, marking them for removal.
"We wanted to see if these two systems work together, so we mapped all the m6a methylation sites in human T cell mRNAs before and after the cells are activated," says Dr Iosifina Foskolou. "We observed that m6a methylation doesn't just happen randomly, or only in previously known regions: it often takes place near AU-rich elements."
When m6a methylation occurred close to AU-rich elements, the mRNA rapidly degraded. "We refer to these mRNAs as 'meta-unstable'," says Dr Paulo Gameiro. "Together, these two red flags act as a powerful signal to the cell's protein machinery, triggering mRNA breakdown and halting the immune response."
"This system allows the immune system to keep the balance between under-activation and over-activation, making sure T cells operate within a narrow range," adds Professor Johnson.
Opening doors
Dr Iosifina Foskolou's team is continuing to work on this system, investigating how to manipulate these sites to make T cells function better against cancer.
"Because modifying how mRNAs are controlled could help to dampen or boost the immune system, the discovery opens lots of doors," she says. "Finding a way to remove these mRNA markers could fight infections or tumours if the immune system is too weak. Alternatively, increasing the power of these signals could reduce the immune response in autoimmune conditions."
"These unstable mRNAs are responsible for so many diverse functions, from energy production to cell communication," says Professor Jernej Ule.
Now that we've worked out what combination of signals is strongest, researchers could further investigate how this dynamic mRNA regulation helps various immune cells to fight infections or tumours, or exploit it for potential new treatments.
Professor Jernej Ule, Van Geest Professor of Neurodegeneration at King's
The experiments for this paper were carried out primarily at the Crick, the University of Cambridge and Sanquin Research Amsterdam. Dr Foskolou is now at Sanquin, Dr Gameiro is at the Nova University in Lisbon and Professor Johnson is at the Karolinska Institute in Stockholm.
This work was funded by the Wellcome Trust, European Research Council, a Wellcome Trust Principal Research Fellowship, a Knut and Alice Wallenberg Scholar Award, the Swedish Medical Research Council, the Swedish Cancer Fund, the Swedish Children's Cancer Fund, multiple HORIZON-MSCA grants and a NWO-VICI grant. Some involved labs are partly funded by the Dutch Cancer Society.
This article is adapted from an article on the Crick's website about the work.
Meta-unstable mRNAs in activated CD8+ T cells are defined by interlinked AU-rich elements and m6A mRNA methylation was published Nature Communications (https://doi.org/10.1038/s41467-025-67762-w).
