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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

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Congrats Ben on your successful ARC discovery grant

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Monash BDI awarded more than $7m in ARC funding

In the latest round of Australian Research Council (ARC) funding, Monash Biomedicine Discovery Institute (BDI) researchers have been awarded 14 Discovery Project grants, worth more than $7 million.

The funded projects are expected to advance knowledge in a range of areas, from understanding why it is that mammalian eggs have so much mitochondrial DNA to defining how signalling pathways regulate organ size, extracting energy from air and many more innovative research projects.

Announced last week, the ARC’s Chief Executive Officer, Ms Judi Zielke PSM, said that the Discovery Projects scheme supports individual researchers or research teams to innovate and build the ‘new’ knowledge essential for a knowledge-based economy.

Monash University ranked third in the ARC Discovery Projects scheme (DP23).

Professor John Carroll, Director of the Monash BDI, said that the outstanding results speak to the high calibre of researchers at the Institute, and illustrate the strength of BDI’s research initiatives.

“This is an incredible result, demonstrating our ability to deliver positive impact globally through fundamental discovery research. Congratulations to all of our researchers who have been successful at securing this highly competitive funding,” Professor Carroll said.

“I’d also like to thank the ARC for this funding, and to say that our researchers appreciate the timely release of these funding outcomes.”

“It was an incredibly competitive year, and commiserations go to those who missed out,” he said.

Congratulations to the following Monash BDI researchers, who are leading projects that received ARC DP23 funding:

Dr Benjamin Gully
Project title: In depth characterisation of the gamma delta T cell immune synapse

Dr Deepak Adhikari
Project title: Understanding why mammalian eggs have so much mitochondrial DNA

Dr Peter Boag
Project title: Biomolecular condensates in mRNA-regulation in germ cells

Professor John Carroll
Project title: How are sperm mitochondria eliminated after fertilisation

Dr Alex Combes
Project title: Imaging mammalian organogenesis with adaptive optics

Associate Professor Fasséli Coulibaly
Project title: The viral fusosome: a modular machinery for cargo delivery to target cells

Professor Mariapia Degli-Esposti
Project title: Defining novel immune checkpoints controlled by stromal cells

Professor Chris Greening
Project title: Extracting energy from air: mechanism of a bacterial hydrogenase

Dr Rhys Grinter
Project title: Hitting bacteria with a Bam: lectin-Like antimicrobials as new antibiotics

Professor Kieran Harvey
Project title: Defining how signalling pathways cooperate to regulate organ size

Professor Nicole La Gruta
Project title: The role of Lck/CD8 association in negatively regulating T cell activation

Emeritus Professor Helena Parkington
Project title: Understanding uterine contractility for reducing newborn lamb mortality

Professor Stephen Turner
Project title: Visualising chromatin changes in 3 dimensions: super to ultra resolution

Associate Professor Lee Wong
Project title: Histone H3.3-dependent transcriptional control and B cell differentiation

Original article

How T Cells recognise infection or disease

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Monash University researchers have expanded their knowledge of how T cells might recognise infections or disease, providing key insight into how an often-overlooked T cell lineage becomes activated when encountering pathogens such as viruses, bacteria, and cancers.

T cells communicate with other cells in the body in search of infections or diseases. This crosstalk relies on specialised receptors known as T cell receptors that recognise foreign molecular fragments from an infection or cancer that are presented for detection by particular molecules called major histocompatibility complex (MHC) or MHC-like.

In this study, Monash Biomedicine Discovery Institute scientists have expanded the understanding of how a poorly defined class of gamma delta T cells recognises an MHC-like molecule known as MR1. MR1 is a protein sensor that takes cellular products generated during infections or disease and presents them for T cells to detect, thereby alerting the immune system.

These gamma delta T cells play an understudied role within specific tissues around the body including the intestinal tract and may be an important factor in diseases that impact these tissues.

The findings are published today in the Proceedings of the National Academy of Sciences.

The study was co-led by Dr Benjamin S. Gully and Dr Martin Davey with first author Mr Michael Rice from the Monash Biomedicine Discovery Institute.

Mr Rice, a PhD student in the Rossjohn lab, says the more we understand how such cells recognise, interact with and even kill infected, diseased or cancerous cells, the greater informed we are when developing therapies and treatments for a range of conditions.

“Gamma delta T cells are key players in the immune response to infected and cancerous cells, yet we know very little about how they mediate these important functions,” said Mr Rice.

By using a high-intensity X-ray beam at the Australian Synchrotron, the scientists were able to obtain a detailed 3D atomic model of how the gamma delta T cell receptor recognises MR1. What sets these cells apart from others seems to be the unusual ways in which they interact with MR1. This work further recasts our understanding of how T cell receptors can interact with specialised MHC-like molecules and represents a notable development for our understanding of T cell biology.

Mr Rice stated: “By using high-resolution protein imaging and biochemical assays, we were able to identify key mechanisms that govern gamma delta T cell receptor recognition of MR1, a key sensor of bacterial infection.”

Co-lead author Dr Gully said: “These cells have evaded characterisation for a long time, leading to many assumptions on how they become activated. Here we have shown that these gamma delta T cells can recognise MHC-like molecules in their own unique ways and in ways we could not have predicted.

“These results will now inform our attempts to understand the roles of these gamma delta T cells within the tissues in which they are found,

Pictured (L-R): Co-lead author Dr Martin Davey, PhD student and first author Mr Michael Rice, Co-lead author Dr Benjamin Gully

Pictured (L-R): Co-lead author Dr Martin Davey, PhD student and first author Mr Michael Rice, Co-lead author Dr Benjamin Gully

and in deciphering their roles within disease.”

Dr Davey said: “These are important T cells that form a major component of the immune system within human tissues such as the lungs and gastrointestinal tract. With a greater understanding of how our immune system operates within these tissues, we can reveal crucial insight into disease.

“A better understanding of these tissue-specific T cells could reveal their power as a new line of immunotherapies for infection and cancer immunotherapy.”

The study represented a cross-disciplinary collaboration between researchers from the Peter Doherty Institute for Infection and Immunity, Monash Centre for Innate Immunity and Infectious Diseases and Monash University. The research findings involved collaborative support from Australian scientists, the ARC Centre of Excellence in Advanced Molecular Imaging, and the use of the Australian Synchrotron. This research was supported by funding from the Rebecca L. Cooper Medical Research Foundation, the National Institute of Allergy and Infectious Diseases of the NIH, National Health and Medical Research Council and the Australian Research Council.

Read the full paper in PNAS titled “Recognition of the antigen-presenting molecule MR1 by a Vδ3+ γδ T cell receptor.”
DOI: 10.1073/pnas.2110288118

Original article