Where there is smoke …. there is fire – Congrats to co-first author Wael

Researchers discover how cigarette smoke impairs critical lung immune cells

Cigarette smoking is widespread and deadly, yet our understanding of how cigarette smoke actually causes serious respiratory illnesses in incomplete, which has severely hampered the development of effective treatments. In the Journal of Experimental Medicine (JEM) Australian researchers reveal how multiple chemicals found in cigarette smoke and e-cigarettes alter the function of a key type of immune cell found in the lungs.

The study suggests that these alterations make cigarette smokers, and those exposed to second- and third-hand smoke, more susceptible to respiratory infections, and exacerbate smoking-related inflammatory diseases such as chronic obstructive pulmonary disease (COPD).

Cigarette smoking is known to impair the immune system’s response to infections and promote inflammation in the lungs that can lead to or exacerbate COPD, the third leading cause of death worldwide. COPD patients are more susceptible to influenza infections that can, in turn, exacerbate the underlying disease by increasing airway inflammation and promoting the destruction of the lung’s air sacs. There are currently no effective treatments for COPD.

According to Dr Wael Awad, from Monash University’s Biomedicine Discovery Institute, until now the mechanisms underlying the skewed immune responses in people exposed to cigarette smoke, and how they are related to smoke-associated diseases like COPD remain unclear,” says Dr Awad, first author on the new JEM study.

Professor Jamie Rossjohn of Monash University’s Biomedicine Discovery Institute co-led the study with Professor David P. Fairlie of the Institute for Molecular Bioscience at University of Queensland, Professor Alexandra J. Corbett of the University of Melbourne, based at the Peter Doherty Institute for Infection and Immunity, and Professor Philip M. Hansbro of the Centenary Institute and University of Technology Sydney.

In their study, the researchers looked at the effects of cigarette smoke on Mucosal-Associated Invariant T (MAIT) cells, a type of immune cell found in the lungs and other tissues of the body. MAIT cells help fight off bacterial and viral infections and can promote inflammation or tissue repair.

MAIT cells are activated by a protein called MR1 that is found in almost every cell of the body. MR1 recognizes chemicals produced by bacteria and presents them at the surface of infected cells in order to activate MAIT cells and initiate an immune response. “We suspected that some of the more than 20,000 chemicals present in cigarette smoke that smokers inhale might also bind to MR1 and influence the activity of MAIT cells in the lungs”, Dr Awad said.

The researchers used computer modeling to predict which components of cigarette smoke might be recognized by MR1 and then found that several of these molecules not only bound to the protein but also either increased or decreased in amounts on the surface of cells. These chemicals, including benzaldehyde derivatives that are also used as flavorings in e-cigarettes, blocked activation of human MAIT cells by compounds produced by bacteria.

Unveiling the Molecular Impact of Smoking on Lung Health. This illustration explores how smoke components in cigarette and e-cigarette smoke obscures critical chemicals that bind MR1 and disrupt T cell functions in the lungs. Image: Erica Tandori

The research team then studied the effects of cigarette smoke on MAIT cells from human blood and mice and showed they reduced MAIT cell function. Mice repeatedly exposed to cigarette smoke developed symptoms of lung disease and this was worsened if also infected by influenza. Researchers found that long-term exposure to cigarette smoke altered the protection provided to mice by their MAIT cells, making them less able to fight off influenza infections and more prone to the development of COPD disease.

“We found that mice lacking MAIT cells were also protected from cigarette smoke-induced COPD, showing reduced levels of lung inflammation and no tissue deterioration in their lung’s air sacs” Profesor Hansbro said.  “This study demonstrates the power of collaboration and the insights we can gain with inter-disciplinary science,” Professor Corbett said.

“Overall, our study reveals that components of cigarette smoke can bind to the protein MR1 and reduce the functions of protective immune cells called MAIT cells. This increases susceptibility to infections worsens progression of lung disease” Awad says. The researchers now plan to investigate exactly which MAIT cell pathways are impacted by cigarette smoke, in order to learn how to better treat COPD and other lung diseases.

Read the full paper in Journal of Experimental Medicine: Cigarette smoke components modulate the MR1-MAIT axis. DOI: 10.1084/jem.20240896

Original article

Other related articles:

postdoc

Unlocking the potential to better target cancer with immunotherapy

Monash University-led research is unlocking new ways for immunotherapy to better target cancer.

Cancer immunotherapy has revolutionised treatment for patients, whereby the body’s own immune system is harnessed to destroy cancer cells.

Typically, several molecules restrain the ability of T cells to target cancer cells and developing approaches to limit this restraining effect can lead to improved effectiveness of cancer immunotherapy.

Research published in Science Immunology has determined the structure of how an inhibitory molecule, LAG3, interacts with its main ligand and provides a new targeted approach to improving the effectiveness of immunotherapy for certain forms of cancer.

The publication is the first to show the crystal structure of a human LAG-3/HLA-II complex and provides a better foundation for development of blocking LAG-3 therapeutics.

Led by Professor Jamie Rossjohn at Monash University’s Biomedicine Discovery Institute (BDI), in collaboration with Immutep, this research resolves how the human LAG-3 receptor binds to HLA II molecules.

First author Dr Jan Petersen said: “The way the PD-1 and CTLA-4 immune checkpoint molecules bind to their respective ligands has been resolved for many years.

“However, the resolution of the interface between another important checkpoint molecule, LAG-3, and its main ligands, HLA-II molecules, has remained elusive.

“Solved using data collected at the Australian Synchrotron, a structure of a LAG-3/HLA-II complex provides a structural foundation to harness rationally for future development of antibodies and small molecule therapeutics designed to block LAG-3 activity.”

A diagram of a cell

Description automatically generated with medium confidence

Figure 1: Human LAG-3 homodimer (with domains D1, D2, D3 and D4) binding to two separate HLA-II (MHC-II) molecules on the surface of an antigen-presenting cell (APC), imposing a distinct 38° offset angle.

Dr Frédéric Triebel, Immutep’s CSO, added: “These findings add to the strong foundation of our work with Professor Rossjohn and his team to develop a deeper understanding of the structure and function of the LAG-3 immune control mechanism, particularly as it relates to our anti-LAG-3 small molecule program.”

Read the full paper published in Science Immunology, titled Crystal Structure of the Human LAG-3–HLA-DR1–Peptide Complex 

 

About the Monash Biomedicine Discovery Institute
Committed to making the discoveries that will relieve the future burden of disease, the Monash Biomedicine Discovery Institute (BDI) at Monash University brings together more than 120 internationally-renowned research teams. Spanning seven discovery programs across Cancer, Cardiovascular Disease, Development and Stem Cells, Infection, Immunity, Metabolism, Diabetes and Obesity, and Neuroscience, Monash BDI is one of the largest biomedical research institutes in Australia. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery.

About Immutep
Immutep is a clinical-stage biotechnology company developing novel LAG-3 immunotherapy for cancer and autoimmune disease. We are pioneers in the understanding and advancement of therapeutics related to Lymphocyte Activation Gene-3 (LAG-3), and our diversified product portfolio harnesses its unique ability to stimulate or suppress the immune response. Immutep is dedicated to leveraging its expertise to bring innovative treatment options to patients in need and to maximise value for shareholders. For more information, please visit www.immutep.com.

DOI: 10.1126/sciimmunol.ads5122

Original article

Monash study unravels another piece of the puzzle in how cancer cells may be targeted by the immune system

Effective immunity hinges on the ability to sense infection and cellular transformation. In humans, there is a specialised molecule on the surface of cells termed MR1. MR1 allows sensing of certain small molecule metabolites derived from cellular and microbial sources; however, the breadth of metabolite sensing is unclear.

Published in PNAS, researchers at the Monash University Biomedicine Discovery Institute (BDI) have identified a form of Vitamin B6 bound to MR1 as a means of engaging tumour-reactive immune cells. The work involved an international collaborative team co-led by researchers from the University of Melbourne.

 

Monash BDI authors on the study (L-R): Dr Patricia Illing, Dr Wael Awad, Dr Mitchell McInerney .

Monash BDI authors on the study (L-R): Dr Patricia Illing, Dr Wael Awad, Dr Mitchell McInerney .

According to Dr Illing, “Our findings suggest that Vitamin B6 molecules displayed by MR1 represent a means for the immune system to detect altered cellular metabolism/metabolite levels that may distinguish cancer cells,” she said.

“Identification of small molecules/metabolites able to activate immune cells with cancer reactivity is a key step in understanding how small molecule sensing might contribute to anti-cancer immunity.”

Central to this study were the unbiased mass spectrometry analysis of small molecules bound to MR1, the structural resolution of the interactions between MR1 and Vitamin B6, and immunological assays performed by lead authors Dr Mitchell McInerney and Dr Wael Awad at Monash Biomedicine Discovery Institute, and Dr Michael Souter and Mr Yang Kang at the University of Melbourne, Peter Doherty Institute.

While it’s not yet clear if the Vitamin B6 molecule can be utilised in therapeutics, “understanding the breadth of MR1 mediated immunity has the capacity to illuminate routes for therapeutic intervention,” Dr Illing said.

An important aspect of the finding is that MR1 differs very little across individuals – with few known genetic variants in the human population. “Thus, understanding immune activation mediated via MR1 may pave the way for therapeutic interventions with broad utility,” Dr Illing said.

She added that next steps for investigation will confirm whether Vitamin B6 and related molecules are displayed by the MR1 of cancer cells at altered levels to healthy body cells, thus enabling specific cancer targeting, or if other small molecules displayed by MR1 may help differentiate cancerous and healthy cells.

Read the full paper published in PNAS, titled MR1 presents vitamin B6–related compounds for recognition by MR1-reactive T cells
DOI: 10.1073/pnas.2414792121

Original article

Congrats Camilla on your co-1st author Cell paper

Ancient gene offers new clue to disease susceptibility for First Nations people

A world-first discovery has identified a previously unknown gene variant influencing first-line immune defences in First Nations people – who are at higher risk of severe respiratory viral diseases – and offers insights for improved disease prevention strategies.

An international team of researchers, co-led by Monash University and the Peter Doherty Institute for Infection and Immunity (Doherty Institute), has gained new understanding of the immunity of First Nations people across Oceania, which includes Australasia, Melanesia, Micronesia and Polynesia.

Published in Cell today, the eight-year project was the first of its kind to comprehensively map a component of the first line immune defences, termed natural killer cells, in Oceania’s First Nations populations, including First Nations Australians.

Natural killer cells are part of the body’s first line of defence against pathogens, which can restrict viruses from replicating in the earliest stages of infection. This is crucial because they can either eliminate low level infection completely or buy time for the generation of virus-specific immunity. Consequently, these immune cells play a key role in an individual’s ability to both prevent infection and recover from a virus.

First Nations people globally, including Aboriginal and Torres Strait Islander people, are at high risk of severe respiratory viral diseases, including COVID-19, pandemic influenza and seasonal influenza. In addition to social determinants of health, genetic variations within immune cells may contribute to the increased risk.

In partnership with Menzies School of Health Research (Northern Territory), the University of Colorado and Stanford University, the researchers evaluated natural killer cells in First Nations people, conducting in-depth genomic and molecular analyses at the Stanford University genomic facility and the Australian Synchrotron.

Dr Camilla Faoro, co-first author of the study from Monash University’s Biomedicine Discovery Institute, used the Australian Synchrotron to provide detailed structural insights into the impact of killer cell immunoglobulin-like receptors found in First Nations Peoples at the molecular level.

“We have shown how the Indigenous and Māori forms of KIR3DL1 interact with the most common HLA molecules in Oceania, which explains why they bind more tightly than the KIR3DL1 forms predominant in other parts of the world,” Dr Faoro said. “This tighter binding changes the capacity of natural killer cells to sense and respond to infection.”

Monash BDI’s Dr Camilla Faoro, co-first author on the Cell publication.

Monash BDI’s Dr Camilla Faoro, co-first author on the Cell publication.

The University of Melbourne’s Professor Katherine Kedzierska, Head of the Human T Cell Laboratory at the Doherty Institute and co-senior author of the paper, has been co-leading the research since 2016.

“Natural killer cells, a type of white blood cell, are key in mediating early immune control against a broad range of viruses,” Professor Kedzierska said. “We focused our research on the origin, distribution and functions of killer cell immunoglobulin-like receptors in First Nations people, as these receptors are crucial components that direct immune responses following viral infections.”

Specifically, the study examined a highly variable natural killer cell receptor, called KIR3DL1, of which there are over 200 forms in humans, capable of binding to subsets of a person’s human leukocyte antigens (HLA) molecules, which present viral peptides for recognition by immune cells, and are themselves highly variable.

Professor Kedzierska said that, critically, the team identified an ancient variant of the natural killer receptor that appears to be exclusive to the people of Oceania, binding more strongly to the HLA variants that are common to Oceanic peoples.

“Our analyses of over 1,300 individuals revealed that the frequency of this Oceanic variant was as high as 28 per cent among highland Papuans and around six per cent in First Nations people from Northern Australia, which could influence susceptibility to infection,” she said.

She noted that genetic and immunological studies often do not involve First Nations and other minority populations around the world.

“Recent studies including this one, underscore the importance of inclusively working with First Nations peoples. Our learnings may inform the design of new vaccines or vaccine regimens and immunotherapies, helping to ensure these agents are effective for the broad sweep of human populations,” she said.

The University of Melbourne’s Professor Andrew Brooks, Head of the Natural Killer Cell Laboratory at the Doherty Institute and a co-senior author of the paper, said the extent to which natural killer cells can respond to viral infections and cancer is dictated by these genes, which are among the most variable in the human genome.

“At a global level, genetic differences contribute to population-specific immune variation, so gaining insights into these differences is important for both addressing and reducing disparities in health outcomes,” Professor Brooks said.

“An understanding of this diversity is key not only to explain why responses to viral infections differ from person to person, but it may also allow us to identify individuals and/or populations at higher risk of severe disease.”

Additional information:

  • Peer review: Norman, PJ, et al. An archaic HLA class I receptor allele diversifies natural-killer-cell-driven immunity in First Nations peoples of Oceania. Cell (2024). DOI: 10.1016/j.cell.2024.10.005
  • Funding: This study was supported by the Australian Research Council and NHMRC.
  • Collaboration: This study was led by Katherine Kedzierska, Steven Tong, Andrew Brooks, Jamie Rossjohn and Paul Norman, in collaboration with Monash University, Menzies School of Health Research, University of Colorado and Stanford University.

Original article

Media contacts

Cheryl Critchley
Media and Communications Manager, Monash University
P +61 (0) 477 571 442
cheryl.critchley@monash.edu

Aline Riche
Senior Communications and Media Officer, Doherty Institute
+61 (0) 403 204 336
Doherty-media@unimelb.edu.au

Come visit us at the Coeliac Australia Gluten-free Expo

Coeliac Australia is excited to announce that the Coeliac Australia Gluten-Free Expo is back in Melbourne in 2024!  October 5 and 6

​Don’t miss Australia’s largest 100% Gluten-Free Event in Victoria!  It’s a fantastic opportunity to learn, taste, and shop the latest in gluten-free food.  With many exhibitors offering show specials, attendees can grab a bargain while discovering new and delicious options. You don’t want to miss this exciting event!

What’s on

Come find us at the Rossjohn lab – Monash Sensory Science stand.

We are delighted to be part of the Coeliac Australia’s Gluten-Free Expo! We are autoimmune disease researchers, especially coeliac disease. We have created artworks, tactile models, and multisensory science books containing audio visualisation of cellular activity for blind, low vision and diverse communities. Come and see us at the Health Hub where you’ll be guided through a tactile journey from gluten to the development and pathology of coeliac disease.

Gluten is more than just an allergy! Join us to explore how gluten triggers a pro-inflammatory immune response and its impact on patient health and quality of life

Education Stage

Gain valuable insights on managing a gluten-free diet and the latest research in coeliac disease.

Fun for the Kids

Enjoy activities designed for our younger attendees.

Sample, Taste, and Shop

Discover a fantastic lineup of exhibitors and food vendors ready to tantalise your taste buds.

For more information visit here.

Buy tickets here.