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Congrats Ben and team on your Nature paper

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Structure of a key “trigger” of the 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 started. The 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 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 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, they are emerging as key players in immune defence and are becoming increasingly important for immunotherapy.

Figure. The image shows the unusual, flexible arrangement of the γδ TCR versus the αβ TCR. B-cell receptor is expressed by antibody-making B-cells.

The team determined the molecular structure of the TCR found on the surface of γδ T cells using cryogenic electron microscopy. This technically demanding project took over a decade from conception to completion and was made possible by the expertise within the Monash Ramaciotti Centre for Cryo-Electron Microscopy.

The new structure unexpectedly showed that the γδ TCR is remarkably flexible, in stark contrast to relatively rigid αβ TCRs. The work also showed that the γδ TCR is very likely the more primeval receptor and completes the initial structural analysis of Burnet’s “trigger” receptors, alongside companion paper also published in Nature.

“This flexibility is key to the ability of the γδ TCR receptor to recognise a wide array of binding partners, which underscores the unique role it plays in the human immune system”, Dr Benjamin Gully of the Monash Biomedicine Discovery Institute, co-first author of the study stated.

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

“The new structure helps constrain theories of how TCRs trigger lymphocytes, and should be helpful, especially, for re-engineering TCRs and optimising their use in the clinic” he said.

The authors would like to acknowledge support from the Australian Research Council Discovery Program which made this basic research project possible.

Read the full paper in Nature: Structure of a fully assembled γδ T-cell antigen receptor.

DOI: 10.1038/s41586-024-07920-0

Some of the Monash University co-authors on the Nature publication (left to right): Liam Rashleigh, Michael Rice, Dr Benjamin Gully, Dilshan Gunasinghe, Professor Jamie Rossjohn, Hari Venugopal.

 

Original article

Congrats Jamie on your Visiting Professor appointment at the University of Oxford

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Welcome to the new RDM Visiting Professors

RDM warmly welcomes two new Visiting Professors this term:

  • Jamie Rossjohn joins the department as Visiting Professor of Structural Immunology, and
  • Martin Young joins as Visiting Professor of Cardiac Science.

Professor Rossjohn travelled over the border from Wales to undertake his undergraduate degree and PhD at Bath University. After pursuing his PhD where he was exposed to the world of X-ray crystallography, he was awarded a Royal Society Fellowship (1995) to work at St. Vincent’s Institute of Medical Research (SVIMR), Melbourne, Australia where he explored detoxifying enzymes and studied bacterial toxins like aerolysin and perfringolysin O (PFO); his work on PFO revealed the molecular mechanism of these toxins. In 2002, Prof Rossjohn moved to Monash University, establishing the Protein Crystallography Unit, which has grown to include over 100 researchers. He played a key role in designing and establishing a fully-automated crystallisation facility.

As a laboratory head and current NHMRC Investigator Fellow, Prof Rossjohn’s research is centred on understanding immunity. He has used structural biology to explain pre-T-cell receptor (TCR) self-association in T-cell development, and how the TCR specifically recognises polymorphic human leukocyte antigen (HLA) molecules in the context of viral immunity and aberrant T-cell reactivity. He has unearthed structural mechanisms of HLA polymorphism impacting on drug and food hypersensitivities, as well as Natural Killer cell receptor recognition. He has pioneered the molecular understanding of lipid-based immunity by T cells, revealing that it can differ fundamentally from peptide-mediated adaptive immunity.

Recently, he has provided a structural basis of how vitamin B metabolites can be presented and recognised by the immune system, revealing a new class of antigen. Collectively, he has published > 500 papers and mentored numerous researchers towards obtaining higher degrees and nationally competitive fellowships.

His multidisciplinary approach, supported by a broad network of collaborators has led to a fundamental advancement of knowledge in this field and his research leadership has been recognised by numerous national and international awards. In 2022, Prof Rossjohn was elected as a Fellow of the Royal Society and Associate Member of EMBO.

Professor Young received his bachelor’s and master’s degrees, and DPhil in Biochemistry at Oxford (Oriel College and Green College). Following postdoctoral training at Boston University and the University of Texas-Houston, he held faculty appointments at the University of Texas-Houston and Baylor College of Medicine, before joining the University of Alabama at Birmingham in 2009 where he is currently a Professor of Medicine and the Jeanne V. Marks Endowed Chair of Cardiovascular Disease.

Research in Prof Young’s laboratory is focused on understanding how environmental factors, such as time-of-day and nutrition, influence cardiometabolic and cardiovascular health. Regarding time-of-day, the laboratory has been actively exploring how an intrinsic time-keeping mechanism, known as the circadian clock, influences cardiac function. His pioneering studies have resulted in a new field, which intersects chronobiology with cardiovascular research.

In addition to his research success, Prof Young has remained firmly committed to training future generations of both physicians and scientists. This has been achieved, in part, through directing both medical school courses, as well as postdoctoral training programmes. As a Visiting Professor of Cardiac Science at RDM, Prof Young will lend his unique expertise in cardiovascular disease and circadian biology to augment both ongoing and nascent research programmes, as well as facilitate the training of graduate students and postdoctoral fellows.

 

Original article