Structure of key ‘trigger’ of immune response solved

An international collaboration involving researchers from Monash University and the University of Oxford has led to a breakthrough in our understanding of how immune responses are triggered. The study was published in Nature.

The human immune system is made up of several important white blood cells (lymphocytes), including B cells and T cells that fight infections and cancers. Fundamental discoveries that have led to the development of immunotherapies and vaccines.

There are two types of T cells in humans, called αβ T cells and γδ T cells, each of which expresses on their surface either an αβ T cell receptor (TCR) or a γδ TCR, respectively.

In 1957, Frank Macfarlane Burnet, a famous Australian immunologist, predicted the existence of these receptors and hypothesized that they would “trigger” clonal expansions of lymphocytes, producing enough cells to fight infections.

We now know that TCRs play an essential role in the recognition of molecules derived from foreign pathogens or tumors. Although γδ T cells are less well known than αβ T cells, they are emerging as key players in immune defense and are becoming increasingly important for immunotherapy.

The team determined the molecular structure of the TCR present on the surface of γδ T cells using a technique called cryogenic electron microscopy. This technically demanding project took more than a decade from conception to completion and was made possible by the expertise of the Monash Ramaciotti Centre for Cryogenic Electron Microscopy.

The new structure unexpectedly showed that the γδ TCR is remarkably flexible, in contrast to the relatively rigid αβ TCRs. The work also showed that the γδ TCR is most likely the most primitive receptor and complements Burnet’s initial structural analysis of the ‘trigger’ receptors, alongside a companion paper also published in Nature.

“This flexibility is critical to the ability of the TCR γδ receptor to recognize a wide range of binding partners, underscoring the unique role it plays in the human immune system,” said Dr. Benjamin Gully, co-first author of the study.

According to Professor Simon Davis, from the University of Oxford and co-senior author of the study, γδ T cells are becoming increasingly important therapeutically.

“The new structure helps constrain theories about how TCRs trigger lymphocytes, and should be useful, in particular, for reengineering TCRs and optimizing their use in the clinic,” he said.