Removing the receptor

Hayday teamed up with Miguel Muñoz-Ruiz, a former postdoc in his lab who now leads his own research program at Complutense University of Madrid. Together, their teams studied the genetic and functional consequences of removing the γδ T cell receptor.

Nicolas Veland in Hayday's lab and Bethania Garcia-Cassani in Muñoz-Ruiz's team examined mice in which the receptor could be deleted from selected populations of mature γδ T cells residing in tissues. The receptor turned out to be essential for the cells' ongoing surveillance work.

The cells did not disappear. After researchers removed the receptor, γδ T cells remained present in tissues, but their behavior changed. The scientists observed altered activity in genes involved in activation, tissue surveillance and communication with other immune cells. They also saw disruption of receptors associated with innate immune responses.

Veland then extended the work to human cells, using CRISPR gene editing to disrupt a gene encoding part of the γδ T cell receptor in laboratory-grown human γδ T cells. Removing the receptor changed gene activity and reduced the expression of several innate-associated receptors, echoing the mouse results.

A blow to cancer surveillance

The teams also tested what happens to cancer control. In mouse models of skin cancer and colorectal cancer, loss of the γδ T cell receptor impaired the animals' ability to restrain tumor development. In further laboratory experiments, receptor-deficient human γδ T cells were less able to restrict the growth of melanoma and colorectal cancer cells.

"This work came from a shared question that Adrian and I kept coming back to," says Muñoz-Ruiz. "If γδ T cells are so rapid and so innate-like, what is their receptor doing? We've shown that without receptor signaling, γδ T cells are much less able to carry out rapid tissue surveillance, showing that responses previously thought to be independent of adaptive immune recognition still rely on the γδ T cell receptor in real time."

What it means for therapy

For cancer immunotherapy, the findings carry a practical implication: γδ T cell treatments may depend on preserving or activating the receptor signal that helps the cells recognize and respond to damage and disease.

"These findings are incredibly important if we want those cells to attack tumors effectively," adds Hayday.

The results also suggest something deeper about immunology itself. "This work also points to a fundamental shift in how immune responses are understood," Hayday says. "These cells defy the traditional classifications of immunity. This is an adaptive receptor being used as part of the innate immune response. That may be why γδ T cells can be found across many different species: they offer an essential and unique form of surveillance that does not fit neatly into either category."

As with any laboratory study, the findings come with limits. The cancer results draw on mouse models and cell cultures, not patient trials, and the human experiments used cells grown in the lab rather than cells taken from living tissue. Whether the same receptor dependency holds in patients receiving γδ T cell therapies remains to be tested. Still, the study gives researchers a clearer mechanistic picture of what keeps these hybrid cells ready for action — and a warning for anyone designing therapies that might disrupt it.

Publication details: Miguel Muñoz-Ruiz et al., "γδ T cell receptor dependencies define a unique immunosurveillance modality," Nature (2026). DOI: 10.1038/s41586-026-11076-4.