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.
Cytokines released by T cells after encountering cancer cells. Credit: Iosifina Foskoulo.
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.
Molecular biologist Jernej Ule runs a lab across the Crick, the UK Dementia Research Institute and King’s College London, 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,” says Jernej.
In a new study published today in Nature Communications, Jernej joined forces with Randall Johnson and 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 Iosifina Foskolou (Cambridge) and Paulo Gameiro (Crick) continued the work, leading teams in their new organisations, Sanquin in Amsterdam and the NOVA University in Lisbon.
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 Iosifina. “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 Paulo. “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 Randall.
Iosifina’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 Jernej. “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.”
