Higher density mediates receptor activation in immune cells

Researchers from the Antibody and Vaccine Group at the University of Southampton have discovered how tumor necrosis factor receptors (TNFR), a crucial class of immune receptors, are activated.

Image Credit: University of Southampton.

The study investigated this group of receptors present on immune cells. Such receptors, like CD40, OX40, and 4-1BB, play a vital role in supporting the immune system to fight against cancer cells and pathogens. The study was published in the Communications Biology journal on June 23^rd, 2021.

As such, antibody drugs that are developed to specifically target and trigger these receptors, known as agonists, have been designed to treat cancer.

To design optimal drug formats, it is crucial to understand the mechanism through which the receptors are triggered on the surface of the cell. But to date, it is yet to be fully understood. Prior studies have demonstrated that receptor clustering—that is, the redistribution of receptors scattered across the cell surface into localized clusters—is vital for the activation of TNF receptors. It is generally believed that more potent activation is induced by larger clusters.

This latest study was headed by Dr. Ben Yu and Professor Mark Cragg from the Centre for Cancer Immunology, along with collaborators from the University and ONI UK. The researchers used a set of exclusive reagents, produced at the University of Southampton, which target CD40, OX40, and 4-1BB. They also employed a new super-resolution microscopy procured through financial support from the Mark Benevolent Fund to find out how receptor activity is mediated by differential receptor clustering.

The study results confirmed that the activation of TNF receptors indeed requires receptor clustering. But fascinatingly, they refuted the widely held belief that more receptor activation is induced by larger clusters. But instead, the study found that agonists that triggered smaller clusters, but with a higher density of receptors, mediated improved TNF receptor activity when compared to those which triggered larger clusters.

Besides the size of the receptors, the research work also revealed that one of the most powerful antibody agonists that target CD40 also induced a unique rod-shaped clustering structure. This may explain the super-agonistic nature of that specific antibody.

The results provide a substantial understanding of how the TNF receptor cluster mediates the activation of the immune system and will help guide the upcoming development of therapeutic antibodies that target TNF receptors.