Immune kill switch safeguards the balance of T cell responses

In an international collaboration between Sanquin, the University of Cambridge and the Francis Crick Institute in London, Iosifina Foskolou and colleagues have uncovered a fine-tuned molecular mechanism that helps T cells maintain this delicate balance. The findings, published in Nature Communications, provide new insights into how immune responses are switched off as precisely as they are switched on, and point towards strategies to improve immunotherapy.

T cells are central players in immune defense. Upon activation, they must swiftly induce specific gene programs to produce cytokines—signaling proteins that orchestrate immune attacks. However, this inflammatory response needs to be tightly controlled. If it persists for too long, the immune system can become pathogenic, attacking healthy tissue and leading to autoimmune disease.

Tight control at the level of RNA

The speed with which T cells activate and deactivate is closely linked to the regulation of messenger RNA (mRNA), the molecules that carry genetic instructions for protein production. Foskolou and her international collaborators investigated how T cells control the lifespan of these mRNA transcripts. While part of the experimental work was conducted during her time in Cambridge, Foskolou now continues this research at Sanquin, where she focuses on translating fundamental insights into clinically relevant applications.

Converging decay signals

The team discovered that two distinct mRNA decay signals act cooperatively to enforce rapid shutdown of cytokine production. These include AU-rich elements within the mRNA sequence and a chemical modification known as m6A methylation. When located in close proximity, these signals markedly accelerate mRNA degradation, effectively extinguishing the immune response.
“This combination functions as a powerful switch,” Foskolou explains. “It ensures that T cells operate within a narrow functional window—potent enough to eliminate infected or malignant cells, but restrained enough to prevent collateral damage.”

New opportunities for immunotherapy

At Sanquin, Foskolou and her group are now exploring how this RNA regulatory system can be manipulated to improve T cell function in cancer, as part of her recently awarded NWO VIDI grant. In particular, they are investigating whether adjusting mRNA stability could help T cells remain active and metabolically fit for longer periods within the hostile tumor environment.

These insights are highly relevant for cellular immunotherapies such as CAR T-cell therapy, in which T cells are engineered to act as living drugs. More broadly, understanding how mRNA decay shapes immune responses may enable targeted strategies to either boost immunity when it is insufficient, or dampen it in the context of autoimmune disease—paving the way for more precise and effective treatments.

Find the article in Nature Communications