Protective Immune Cells’ Function Altered by Cigarette Smoke Components

Cigarette smoking is prevalent worldwide and causes numerous diseases, yet our understanding of how cigarette smoke (CS) causes serious respiratory illnesses is incomplete, and has held back the development of effective treatments. Researchers headed by a team at Monash University’s Biomedicine Discovery Institute carried out a preclinical study showing how multiple chemicals found in cigarette smoke and in e-cigarettes alter the function of a key type of immune cell found in the lungs.

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

First author Wael Awad, PhD and colleagues reported their results in Journal of Experimental Medicine, in a paper titled “Cigarette smoke components modulate the MR1-MAIT axis.” The research was co-led by Jamie Rossjohn, PhD, at Monash University’s Biomedicine Discovery Institute, together with Professor David P. Fairlie, PhD, at the Institute for Molecular Bioscience at the University of Queensland, Alexandra J. Corbett, PhD, at the University of Melbourne based at the Peter Doherty Institute for Infection and Immunity, and Philip M. Hansbro, PhD, at the Centenary Institute based at the University of Technology, Sydney.

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, which the authors noted is the third leading cause of chronic morbidity and death worldwide, according to a WHO report. COPD patients are more susceptible to influenza infections that can, in turn, worsen 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. “… the mechanisms that drive the development and progression of CS-induced chronic inflammation and COPD are poorly understood, and this has severely hampered the development of effective treatments,” the researchers noted.

As Awad also pointed out, “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.”

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. The investigators also stated that, “MAIT cells have recently been reported to be significantly reduced in the peripheral blood of smokers and patients with COPD, yet accumulate in the lungs of COPD patients.”

MAIT cells are activated by an antigen-presenting 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. “MR1 is a ubiquitous molecule that presents bacterial metabolites to MAIT cells, which are highly abundant in the lungs,” the authors further wrote.

Awad commented, “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.” However, as the authors acknowledged, “Whether CS components can bind MR1, impact MAIT cell functions in the lungs, and how they are related to the pathogenesis of COPD are yet to be elucidated.”

Fairlie added, “While we know that smoke from cigarettes, bushfires, cooking, vehicle exhausts and burning waste pose significant health risks, we still surprisingly know relatively little about how the specific components pf smoke affect our immune system and how they impact multiple parts of the human body.”

As part of their reported study the researchers used computer modeling to predict which components of cigarette smoke might be recognized by MR1. They found that several of these molecules not only bound to the protein but also either increased or decreased its amounts on the surface of cells.

These chemicals, including benzaldehyde derivatives that are also used as flavorings in cigarettes, e-cigarettes, blocked activation of human MAIT cells by compounds produced by bacteria. The research team evaluated the effects of cigarette smoke on MAIT cells from human blood and mice, and showed they reduced MAIT cell function.

Through their study the investigators confirmed that mice repeatedly exposed to cigarette smoke developed symptoms of lung disease and this was worsened if also infected by influenza. It was also 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.

“Chronic CS exposure altered MAIT cell phenotype and function and attenuated MAIT cell responses to influenza A virus infection in vivo,” the team wrote, also noting in their paper, that “COPD patients are highly susceptible to influenza that exacerbates their conditions.”

Hansbro added, “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.” In their report the authors in addition stated, “MR1-deficient mice were partially protected from the development of chronic obstructive pulmonary disease (COPD) features that were associated with CS exposure. Thus, CS can impair MAIT cell function by diverse mechanisms, and potentially contributing to infection susceptibility and disease exacerbations.”

Awad concluded, “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 [and] worsens progression of lung disease.” The researchers now plan to investigate exactly which MAIT cell pathways are impacted by cigarette smoke, to help learn how to better treat COPD and other lung diseases. “This study demonstrates the power of collaboration and the insights we can gain with inter-disciplinary science,” Corbett said.