Researchers at the Francis Crick Institute, King's College London and Complutense University of Madrid have shown that γδ T cells use adaptive immune receptors to drive rapid, innate-like responses to tissue stress, inflammation and cancer.
Researchers have long divided the immune system into two broad arms: innate immunity, which responds rapidly and broadly to danger, and adaptive immunity, which learns and builds with time, developing highly specialised receptors to recognise specific threats.
New research published in Nature today challenges that distinction, revealing that γδ T cells depend on an adaptive immune receptor to maintain and mount rapid tissue surveillance responses normally associated with innate immunity.
These specialist immune cells patrol tissues, including the skin and gut, for signs of damage, infection and cancer. Their ability to detect signs of cellular stress and dysregulation, and to respond rapidly to abnormal cells, has made them a promising candidate for next-generation cancer immunotherapies; indeed, there are scores of clinical trials ongoing.
Primed to respond
"There is a lot of interest and progress in using γδ T cells in cancer immunotherapies, or even other types of immune treatment, because they can recognise any kind of dysregulation and act quickly," says Principal Group Leader Adrian Hayday, who has been at the forefront of γδ T cell research for over 40 years.
"But if we are going to use them clinically, we need to understand what underpins that rapid response."
Like other adaptive immune cells, γδ T cells carry signature receptors on their surface that sense signals around them. During development, this helps shape how γδ T cells mature, where they settle in the body and how ready they are to respond to specific stresses.
Adrian and his team wanted to understand whether the job of these so-called "T cell receptors" ended there, as has been widely proposed, or whether mature γδ T cells still needed their T cell receptors to stay primed for rapid tissue surveillance.
He teamed up with Miguel Muñoz-Ruiz, a former postdoc in his lab now leading his own research programme at Complutense University of Madrid. Together, their teams studied the genetic and functional changes resulting from removing the γδ T cell receptor.
Nicolas Veland in Adrian's lab and Bethania Garcia-Cassani in Miguel's team investigated activity in mice in which the γδ T cell receptor could be removed from selected populations of mature γδ T cells that sit within tissues. The researchers observed that the receptor was essential to the cells' continuing tissue surveillance function.
When the receptor was removed, γδ T cells remained present in tissues, but their behaviour changed. The researchers saw alterations in the activity of genes involved in activation, tissue surveillance and communication with other immune cells, as well as disruption to receptors associated with innate immune responses.
Nicolas also undertook key parts of the experimental work in human γδ T cells, using CRISPR to disrupt a gene encoding part of the γδ T cell receptor in laboratory-grown human cells. Removing the receptor altered gene activity and reduced the expression of several receptors associated with innate responses, echoing changes seen in the mouse experiments.
The teams also tested the consequences for cancer surveillance. Across mouse models of skin cancer and colorectal cancer, loss of the γδ T cell receptor impaired control of tumour development. And in further lab 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 Miguel. "If γδ T cells are so rapid and so innate-like, what is their receptor doing?"
"We've shown that without receptor signalling, 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."
Implications for cancer immunotherapy
For cancer immunotherapy, the findings suggest that γδ T cell treatments may depend on preserving or activating the receptor signal that helps them recognise and respond to damage and disease.
"These findings are incredibly important if we want those cells to attack tumours effectively," adds Adrian.
"But this work also points to a fundamental shift in how immune responses are understood. 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."
