Advanced imaging tips T cell target recognition on its head

A team of leading Australian scientists have published research which transforms existing perceptions of T cell recognition.

T cells represent a key component of our immune system, and play a critical role in protecting us against harmful pathogens like viruses and bacteria, and cancers. The more we understand about how they recognise, interact with and even kill infected or cancer cells moves us closer to developing therapies and treatments for a range of conditions.

Dr Edward Giles, Honorary Clinical Associate, Regulation of Interferon and Innate Signalling
Dr Edward Giles, Honorary Clinical Associate, Regulation of Interferon and Innate Signalling

In a paper published today in the premier international journal Science, an Australian team of scientists led by Monash University, Hudson Institute of Medical Research, the Australian Research Council Centre of Excellence in Advanced Molecular Imaging and the University of Melbourne at the Doherty Institute, has redefined what we thought we knew about T cell recognition for the past 20 years.

Hudson Institute’s Dr Edward Giles (Honorary Clinical Associate in Regulation of Interferon and Innate Signalling) provided valuable clinical contribution towards the study.

“It was great to be able to contribute to this ground-breaking work on T cell recognition” said Dr Giles.

“Through a clinical collaboration, we were able to show this new immune interaction in the gut, and suggest a role in coeliac disease. Coeliac disease is an immune-mediated disease affected up to 1 in 70 Australians, and its only treatment is a lifelong strictly gluten-free diet. This new work opens potential new targets for treatment, as well as a deeper understanding of how the immune system recognises targets in the gut and elsewhere.”

In order to interact with other cells in the body, T cells rely on specialised receptors known as T Cell Receptors (TCRs) that recognise virus or bacteria fragments that are bound to specialised molecules called major histocompatibility complex (MHC) or MHC-like. Over the past 20 years, the prevailing view was that TCRs sat atop the MHC and MHC-like molecules for recognition.

The team of scientists characterised a new population within a poorly understood class of T cells called gamma delta T Cells that can recognise an MHC-like molecule known as MR1.

Using a high intensity X-ray beam at the Australian Synchrotron, the scientists obtained a detailed 3D image of the interplay between the gamma delta TCR and MR1 revealing an intriguing result whereby the gamma delta TCR-bound underneath the MHC-like molecule for recognition.

This highly unusual recognition mechanism reshapes our understanding of how TCRs can interact with their target molecules, and represents a major development in the field of T cell biology.

“Think of it like a flag attached to a cell. We always thought the T cells were coming along and reading that flag by sitting atop it. We have determined that instead, some T cells can approach and interact with it from underneath,” said Dr Jérôme Le Nours from Monash Biomedicine Discovery Institute, co-lead author on the paper.

Artwork of a gamma delta T cell receptor interacting with MR1. Artwork: Dr Erica Tandori, Artist in Residence, Department of Biochemistry & Molecular Biology/School of Biomedical Sciences, Monash University.

“These are the types of fine and important details that can change how we approach future research avenues in T cell biology,” said Dr Le Nours.

“This is important because T cells are a critical weapon in our immune system, and understanding how they target and interact with cells is crucial to harnessing their power in therapies such as infection and cancer immunotherapy.”

”Our study shows that MR1 is a new type of molecular target for gamma delta T cells. These cells play a decisive role in immunity to infection and cancer, yet what they respond to is poorly understood. MR1 may be signalling to gamma delta T cells that there is a virus, or cancer cell and triggering these cells to initiate a protective immune response” said Dr Nicholas Gherardin from the Doherty Institute, co-lead author on the paper.

“We’re very excited to follow up these findings in studies that will aim to harness this new biology in disease settings.”

The research findings were a culmination of a six-year project that involved collaborative support from Australian scientists, the ARC Centre of Excellence in Advanced Molecular Imaging, the use of the Australian Synchrotron, and funding from the National Health and Medical Research Council and the Australian Research Council.