Monash researchers make fundamental advance in understanding T cell immunity

Monash University researchers have provided a fundamental advance regarding how T cells become activated when encountering pathogens such as viruses.

The recent study published in Science, co-led by Professor Nicole La GrutaProfessor Jamie Rossjohn and Professor Stephanie Gras with first author Dr Pirooz Zareie from the Monash Biomedicine Discovery Institute, have found that T Cells need to recognise pathogens in a particular orientation in order to receive a strong activating signal.

T cells play a key role in the immune system by eliminating invading pathogens, such as viruses, and it is crucial to understand the factors that determine how and why T cells become activated after recognizing these pathogens.

T cells express on their surface a T cell receptor (TCR) that recognizes and binds to virus fragments (antigens) presented by infected cells.  This recognition event can lead to T cell activation and killing of infected cells.

“The central issue is that there are millions of different T cell receptors (TCRs) in the human body, and a vast array of viruses, making it difficult to understand the rules around how T cell receptor recognition of a virus drives T cell activation. Indeed, it is a problem that has remained contentious for over 25 years” says Professor La Gruta.

“Our study has shown that the orientation in which the T cell receptor binds is a primary factor determining whether the T cell receives an activating signal,” Professor La Gruta said.

“This is an advance in our fundamental understanding of how a T cell needs to ‘see’ pathogenic antigens in order to be activated,” she said. “It has clarified a critical mechanism essential for effective T cell immunity. It is also relevant to the ongoing development of immunotherapies that aim to boost the activation of T cells.”

Dr Pirooz Zareie stated: “a combination of technologies, including super-resolution microscopy, X-ray crystallography at the Australian Synchrotron, biochemical assays and using in vitro and in vivo experimental models from a variety of labs led to the findings.”

The study represented a cross-disciplinary collaboration between researchers from the University of Utah, National University of Singapore, University of New South Wales and Monash University.

TCR-pMHC recognition - through the looking glass. The image shows a brightly colored canonical interaction between TCR and pMHC which is conducive to signal transduction. The faded mirror image shows a reversed TCR-pMHC interaction which is unable to support signal transduction and thus T cell activation. (Created by Dr. Erica Tandori (Rossjohn lab))

TCR-pMHC recognition – through the looking glass. The image shows a brightly colored canonical interaction between TCR and pMHC which is conducive to signal transduction. The faded mirror image shows a reversed TCR-pMHC interaction which is unable to support signal transduction and thus T cell activation. (Created by Dr. Erica Tandori, Rossjohn lab)

Read the full paper in Science titled: Canonical T cell Receptor Docking on peptide-MHC is essential for T cell signaling.DOI: 10.1126/science.abe9124

Original article

Also see ARC Research Highlights

Congratulations to Jia Jia and Claerwen whose study on Rheumatoid Arthritis was published today in Science Immunology

New understanding of the deleterious immune response in rheumatoid arthritis

Researchers within the Biomedicine Discovery Institute (BDI) at Monash University have made a breakthrough in understanding the role played by high-risk immune genes associated with the development of rheumatoid arthritis (RA).

The findings, published in Science Immunology, were the result of a seven-year collaboration led by Monash University, involving Janssen Biotech, Inc., Janssen Cilag Pty Ltd., Janssen Research & Development, LLC and the Karolinska Institute, Sweden.

Certain immune system genes, called Human Leukocyte antigen (HLA)-DR4, cause an increased susceptibility to RA.  In this study, using mice genetically modified to express the human HLA-DR4 molecule, the team examined, at the molecular and cellular levels, how T cells recognise these HLA-DR4 molecules. The team also showed that highly similar T cell receptors, likely with similar recognition characteristics, are also present in “RA-susceptible” humans expressing these HLA molecules.

“This suggests that there may be an immune signature of RA development, providing a potential avenue for diagnostic development or a window of opportunity for therapeutic development,” says Dr Hugh Reid, who co-led the study with Professor Jamie Rossjohn and Professor Nicole La Gruta at Monash University.

With the assistance of the Australian Synchrotron, the researchers were able to determine the structure of the molecular complexes that form during the interaction between T cell receptors and altered joint proteins bound to HLA-DR4. Armed with this information, they were able to work out what was important in this deleterious T cell response.

“This research is an excellent example of how collaborative efforts between major academic and industrial partners can lead to breakthroughs in basic science that in turn provide avenues for the development of better therapeutics for common diseases,” says Dr Reid.

Rheumatoid arthritis is an autoimmune disease affecting about one per cent of the world’s population. It is characterised by swollen, painful, stiff joints, and consequently, restricted mobility in sufferers. By working out how T cells recognise altered joint proteins in complex with ‘susceptibility’ HLA molecules, Monash scientists have advanced our understanding of how these HLA molecules may predispose individuals to the development of disease. The insight provided may greatly assist in achieving the long-term goal of producing personalised medicines and/or preclinical interventions to treat RA.

Read the full paper in Science Immunology titled: The shared susceptibility epitope of HLA-DR4 binds citrullinated self-antigens and the TCR

Original article

See also:

New hope for rheumatoid arthritis sufferers as Melbourne researchers make new discovery

ASBMB Today: Unravelling the mind’s eye — science through a novel lens

Erica’s story and our Sensory Science initiative is featured on page 33 of the April issue of ASBMB Today: Science & Art.

 

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Original story by Kamalika Saha in ASBMB Today : Science & Art 

Congrats Erica on the award of the National Science Week grant ‘My Goodness: Interactive multisensory science books’

Get a taste for science in National Science Week!

Our $500 000 grant round for 2021 has just been announced with great projects from around the country preparing to celebrate science. Many of the projects took inspiration from the National Science Week school theme of Food – Different by Design, including Food – Now and into the Future which is all about making healthy food choices and will be presented by the Wesley Mission in Logan City just south of Brisbane.

STEAM Ahead – Foodlovers is an exploration of traditional Indigenous food and modern food production techniques at the Western Sydney Parkland. If you’re thirsty for more, four boutique brewers will conjure special brews for ExBEERimental Science in Hobart and share their techniques and tastes with both live and virtual audiences.

And while they may not be delicious, the Donut Shooting Robots in Adelaide will fight it out as 15 teams go head to head in a design – build – program competition.

Minister for Industry, Science and Technology Karen Andrews said the Australian Government was proud to support inspiring, innovative and accessible projects as part of National Science Week.

“Science is everywhere, and National Science Week is for everyone,” Minister Andrews said.

“Even in the midst of last year’s lockdowns, more than one million Australians took part in events across every state and territory. This year, we’re looking to boost those numbers even higher.

“From concerts to VR tours and everything in between, this year’s National Science Week grant recipients have something to offer every Australian.”

The grant recipients are:

VIC

My Goodness: Interactive multisensory science books
Monash University

Read about immune system cells through your sense of touch or learn about food and nutrition through a 3D soundscape. ‘My Goodness’, a Rossjohn Sensory Science Multisensory Science Book, is an exhibition of 10 interactive ‘books’ designed for low-vision, blind, hearing-impaired, deaf, and non-disabled audiences.

The Books explore the relationship between infection, immunity, food, and nutrition. They make science accessible to more people by using large print text, braille, tactile artworks, haptic and 3DAudio, visual tracking and tactile sensor interaction technologies.

Original article

National Science Week 2021 will run from 14-22 August. Watch this space for further details.

Discovery of a third T cell lineage

The immune systems of all vertebrates contain specialized cells, called T cells, that play a fundamental role in protecting against fungal, bacterial, parasitic and viral infections. T cells use ‘molecular sensors’ called T cell receptors (TCRs) on their surface that can detect and eliminate the invading pathogens. For most of the past four decades, it was considered that there were only two T cell lineages, αβ and γδ T cells, characterized by their cell surface expressed αβ and γδ TCRs, respectively.

In a paper published today in Science, an international team of scientists at the University of New Mexico (US), Monash University (Australia), and the US National Institutes of Health, has defined a novel T cell lineage, called γµ T cells, found only in marsupials (e.g. kangaroos and opossums) and monotremes (e.g. duckbill platypus).

Evidence for the γμ TCR came with the discovery of genes encoding the TCRμ protein whilst analyzing the first complete marsupial genome, that of the South American opossum Monodelphis domestica.  Oddly, distinct from conventional αβ and γδ TCRs, TCRμ was predicted to share similarity with the antibodies.

Using the Australian Synchrotron, the scientists at Monash University obtained a detailed three-dimensional image of the opossum γµTCR architecture that was unique and distinct from αβ or γδ TCRs. Noteworthy was the presence of an additional single antibody-like segment called Vμ domain with an architecture resembling to nanobodies, a unique type of antibodies. This discovery raises the possibility that γμ T cells recognize pathogens using novel mechanisms, distinct from conventional T cells.

“The discovery of a nanobody like structure in the γμ TCR has the potential to expand the immunology ‘toolbox’. Indeed, nanobodies discovered in the camel family (e.g. alpacas) have recently attracted considerable interests for their development as research and diagnostic tools and more importantly as immunotherapeutics in humans to combat cancer and viral infections such as COVID-19. Marsupials may offer an alternative source of nanobodies, one that is smaller, easier and cheaper to maintain than llamas or alpacas.” said Monash University Dr Marcin Wegrecki from the Biomedicine Discovery Institute, co-first author on the paper.

“Our findings further illustrate the value of exploring the world’s biodiversity for novelty beyond the standard animal research models, such as laboratory mice. Modern genomic tools applied to many species have opened the door to the myriad of immunological solutions to fighting pathogens that evolution has produced.” said Prof Robert Miller from the University of New Mexico, co-lead author on the paper.

“Many in-roads have been made in understanding the immune systems of humans and mice leading to the development of novel immunotherapeutic approaches enabling humans to combat highly pathogenic viruses. However, much less is understood on how immunity operates in other species that, in some cases, have been decimated by wildlife diseases. Ultimately our work may guide the development of veterinary approaches (e.g. novel vaccines) that will contribute to wildlife conservation.” said Dr Jérôme Le Nours from Monash Biomedicine Discovery Institute, co-lead author on the paper.

“This is a prime example of curiosity driven science leading to unexpected and transformative findings.” Le Nours stated.

The research findings were a culmination of a 12-year project that involved a multidisciplinary collaborative effort and the support from the ARC Centre of Excellence in Advanced Molecular Imaging, and funding from the US National Science Foundation, the US National Institutes of Health and the Australian Research Council.

Read the full paper in Science titled: The molecular assembly of the marsupial γμ T cell receptor defines a third T cell lineage.
DOI: 10.1126/science.abe7070

Original article