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

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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:

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

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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

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