How T Cells recognise infection or disease

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

Monash BDI researchers make Highly Cited list for the fourth consecutive year

Two Monash Biomedicine Discovery Institute (BDI) researchers have been recognised for their exceptional research performance, determined by production of multiple highly cited papers that rank in the top one per cent by citations for a field and year.

Professor Jamie Rossjohn and Professor Charles Mackay have each been ranked as a 2021 Highly Cited Researcher in the prestigious list released in November by Clarivate Analytics.

Professor Rossjohn’s research focus is on understanding, at the molecular level, how the T cell receptor specifically recognises polymorphic Human Leukocyte Antigen (HLA) molecules in the context of protective immunity, autoimmunity and other adverse T cell reactivities. Further, he has pioneered the molecular understanding of lipid and metabolite based immunity by T cells that recognise HLA class-I like molecules, CD1 and MR1, respectively. This is the fourth consecutive year that Professor Rossjohn has appeared on the Clarivate Analytics Highly Cited Researcher list.

Professor Mackay has forged a new understanding of the gut microbiome and the important role it plays in immune responses including allergies and in a number of diseases including type 1 diabetes. His research into how immune responses can be manipulated using ‘medicinal foods’, as well as novel gut microbial species, is attracting both clinical and public interest, with the latest research findings moving to clinical trials.

Professor Mackay was highly cited from 2005 to 2010 under what was then the Institute for Scientific Information citation, and has remained on the Clarivate Analytics Highly Cited Researcher list since 2017.

The Highly Cited Researcher list, now in its eighth year, determines the ‘who’s who’ of influential researchers, drawing on data and analysis to identify the world’s leading researchers who have demonstrated significant and broad influence. See the full list of researchers on the Web of Science:  Nineteen researchers from Monash University were recognised this year.

Image: Professor Jamie Rossjohn and Professor Charles Mackay

Original article

The interplay between diet, the microbiota and immunity

Research in mice shows how diet alters immune system function through a gut microbe

At a glance:

  • Research in mice demonstrates how diet alters a gut microbe molecule that in turn prompts immune cells to downregulate inflammation
  • Study illustrates the molecular mechanism behind the longstanding view that diet, microbiota and immunity influence each other in myriad ways
  • Following more testing, findings could inform the design of small-molecule drugs that regulate immune response to treat inflammatory conditions

An international team of researchers including Monash University have found molecular proof of how diet ultimately affects immunity through the gut microbiome.

The team’s work, conducted in mice, have pinpointed a microbial molecule called B. fragilis that sets off an immune-signalling cascade triggered by the host’s diet of a metabolic breakdown of branch-chained amino acids in the mouse gut.

The multistep pathway begins with B. fragilis taking up the branch-chained amino acids and then converting them by a specific enzyme into sugar-lipid molecules that also have branched chains that are then spotted and picked up by a class of immune-signalling cells known as antigen-presenting cells, which in turn induce natural killer T (NKT) cells to exercise their immunoregulatory response through upregulating inflammation-controlling genes and immune-regulatory chemicals.

Furthermore, the team found that B. fragilis alters the structure of the sugar-lipid molecules that it metabolizes and renders them better capable of binding to receptors on specific immune cells and initiating a signalling cascade that culminates in downregulating inflammation.

The findings, published November 10 in Nature, offer a unifying explanation for the complex interplay between diet, gut microbiota and immune function. They are the result of collaboration among scientists at Harvard Medical School, Brigham and Women’s Hospital, Seoul National University, and Monash University in Australia.

NKT cells line the human gastrointestinal tract, the lungs and are also found in the liver and spleen and likely play a significant role in immune regulation and are implicated in a range of inflammatory conditions including ulcerative colitis, and to a possible role in airway inflammatory conditions, such as asthma.

While scientists have surmised for a long time that diet plays a role in immune health, the new study elucidates the precise molecular cascade behind diet and immune health, said study senior author Dennis Kasper, professor of immunology at Harvard Medical School.

“We have shown how diet affects the immune system through a microbe mediator in the gut, and this is a really striking example of the diet-microbiota-immunity triad at play,” Kasper said. “What this work really does is provide a step-by-step pathway from beginning to end that explains how and why this triad works and how diet ultimately affects the immune system.”

Using a structural biology approach, Professor Jamie Rossjohn, ARC Laureate Fellow at the Monash Biomedicine Discovery Institute, elucidated how the lipid structure engages with and binds to antigen-presenting cells—the immune cells that give NKT cells the go-ahead to produce anti-inflammatory chemicals.

“This work offers a great example of trans-disciplinary discovery-based research aimed at answering a major question in biomedical sciences, namely how the immune system can be modulated by the interplay between diet and the microbiota,” Professor Rossjohn said.

Study coinvestigator Seung Bum Park, professor of chemistry at Seoul National University, synthesized and the Harvard team tested 23 different configurations of the microbe-made immunomodulatory molecule to determine how each one interacts with the immune cells that regulate inflammation.

“Our new work demonstrates that the branching of the lipid structure induces a very different response—the branching in the structure induces an anti-inflammatory rather than a proinflammatory response,” Professor Kasper said.

The findings offer the hope that inflammatory diseases mediated by these NKT cells could one day be treated with inflammation-dampening microbial molecules made in the lab, the researchers said.

Co-authors included Sungwhan F. Oh, T. Praveena, Heebum Song, Ji-Sun Yoo, Da-Jung Jung, Deniz Erturk-Hasdemir1, Yoon Soo Hwang, ChangWon Lee, Jérôme Le Nours, Hyunsoo Kim, Jesang Lee, and Richard Blumberg.

Read the full paper (view only)  via SharedIt in Nature titled: Host immunomodulatory lipids created by symbionts from dietary amino acids. 

Original article

Congrats Jamie: Highly Cited researcher again!

Congratulations to Jamie who is again on the Highly Cited Researchers 2021 list of the world’s most Highly Cited Scientists, which is published annually by Clarivate Analytics.

From Clarivate: Recognising the true pioneers in their fields over the last decade, demonstrated by the production of multiple highly-cited papers that rank in the top 1% by citations for field and year in the Web of Science™. Of the world’s scientists and social scientists, Highly Cited Researchers truly are one in 1,000.

Original article

BDI researchers honoured in annual Dean’s Awards

Congratulations to Drs Adam Shahine and Milda Kaniusaite, who have each been recognised with a Dean’s Award for Excellence in 2021 for research carried out at the Monash Biomedicine Discovery Institute (BDI).

Dr Shahine won an award in the Excellence in Research – Early Career Researcher category.

“It was an honour to receive the ECR category for the Dean’s Excellence in Research award,” he said.

Dr Shahine has researched the immune system and its functions regulating and dysregulating immunity in our bodies since 2014 in Professor Jamie Rossjohn’s lab. “This work has provided a number of novel molecular insights into how presentation of lipid antigens plays a role in modulating adaptive immunity,” he said.

The research has been appeared in a number of high quality publications such as ‘Nature Cancer’ and ‘Science Immunology’, and been presented at conferences at places including the UK and US. “And that has all made an impact on the field,” Dr Shahine said. “Building upon this body of work, I was awarded an ARC DECRA Fellowship to continue research in this field to explore uncharted territory.”

Dr Shahine acknowledged the role of Professor Rossjohn in his career successes. “I definitely wouldn’t be where I am today without the mentorship of my supervisor Jamie Rossjohn, the supportive network within the laboratory, as well as collaborators at Harvard,” he said. The Australian Synchrotron has been invaluable, he added.

Dr Shahine is supervising three junior post-doc researchers and three PhD students, as well as conducting his own research.

Biochemist Dr Milda Kaniusaite’s research in the field of discovering new antibiotics earned her a Dean’s Award for Doctoral Thesis Excellence.

She said the exciting interdisciplinary project sought to understand the biosynthesis mechanism of clinically relevant antibiotics such as Teicoplanin and Vancomycin, then, based on these findings, re-engineer the biosynthesis pathway and demonstrate production of altered sequence products.

“This project was highly unique, given the fact that I was able to isolate whole antibiotic biosynthesis mega-enzymatic machinery from bacteria,” Dr Kaniusaite said. “In general, findings from my PhD can be considered as a set of rules that provide novel guidelines for effective biosynthetic pathway re-engineering leading to the synthesis of new molecules,” she said.

“The results from this study appear to be universal and can be relevant to the re-engineering of many other clinically important compounds produced by mega-enzymes. “This I believe will be of great importance in developing new drugs related to the treatment of antibiotic-resistant bacterias,” she said.

Dr Kanuisaite said it was a great pleasure and honour to win the award. “The award motivates and boosts my confidence that I am on the right track being a researcher and working for science. It helps me to open new doors, get new opportunities and gives an additional strength dealing with new and upcoming challenges.”

She is now a post-doctoral researcher at the Institute for Clinical Medicine at the University of Oslo, Norway.

The awards were given to 25 Monash Medicine, Nursing and Health Sciences individuals and team recipients for outstanding achievements in education, research, industry education programs, professional services, and doctoral thesis.

During the virtual event this month, Professor Christina Mitchell AO, Dean of Monash Medicine, Nursing and Health Sciences acknowledged the efforts of all staff and PhD graduates. “I would like to congratulate all of our award winners. You are an amazing group and outstanding in every way. I look forward to congratulating you in person soon,” she said.

Videos of this year’s winners discussing their projects and achievements can be viewed on the Dean’s Award for Excellence website.


About the Monash Biomedicine Discovery Institute at Monash University

Committed to making the discoveries that will relieve the future burden of disease, the newly established Monash Biomedicine Discovery Institute at Monash University brings together more than 120 internationally-renowned research teams. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery.

Original article