Lead Image: The image shows the unusual, flexible arrangement of the γδ TCR versus the αβ TCR. The B-cell receptor is expressed by antibody-making B-cells.
An international collaboration, involving researchers from the laboratories of Professor Jamie Rossjohn at Monash University in Australia, and Professor Simon Davis at the MRC Translational Immune Discovery Unit here in Oxford, has led to a breakthrough in our understanding of how immune responses are started. The resulting study has just been published in Nature.
The human immune system comprises multiple important white blood cells (i.e., lymphocytes) including B cells and T cells that fight off infections and cancers. Basic discoveries leading to an understanding of how lymphocytes function 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 surfaces 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 speculated that they would “trigger” clonal lymphocyte expansions, producing enough cells to fight off infections. We now recognize that TCRs have the pivotal role of recognising molecules derived from foreign pathogens or tumours. While less is known about γδ T-cells than αβ T-cells, γδ T-cells are emerging as key players in immune defence and are becoming increasingly important for immunotherapy.
Using a technique called cryogenic electron microscopy, the team determined the molecular structure of the TCR found on the surface of γδ T-cells. This was a technically demanding study that from conception took several years to complete.
The new structure unexpectedly shows that the γδ TCR is remarkably flexible, in stark contrast to relatively rigid αβ TCRs. The work also shows that the γδ TCR is very likely the more primaeval receptor, and it completes the initial structural analysis of the triumvirate of “trigger”-type receptors anticipated by Burnet, alongside a companion paper from a laboratory in Hangzhou, China, also published in Nature.
Dr Benjamin Gully, co-1st author of the study stated:
This flexibility is key to the ability of the γδ receptor to recognise a wide array of binding partners, which underscores the unique role it plays in the human immune system.
The work in Oxford was led by João Ferreira Fernandes and Mai Vuong, also co-1st authors of the study. According to Dr Ferreira Fernandes, modulating γδ T-cells is becoming an important therapeutic goal. He said:
This structure helps us understand how different classes of TCR can trigger T cells and provides useful insight into how to engineer TCRs to better their therapeutic potential.
Read the full paper here: https://www.nature.com/articles/s41586-024-07920-0
Professor Rossjohn was last year appointed Visiting Professor of Structural Immunology in the Radcliffe Department of Medicine.