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The research, published in the Journal of Experimental Medicine, identified a built-in safety switch that regulates these cells and may prevent them from becoming too active, which could lead to harmful inflammation. This discovery could open new ways to treat a range of health conditions. 

A built-in "kill switch" for immune cells 

Unconventional T cells, which include mucosal-associated invariant T (MAIT) cells, gamma-delta T (γδT) cells and natural killer T (NKT) cells, are highly sensitive to NAD (nicotinamide adenine dinucleotide), a molecule released when cells and tissues are damaged. When NAD is detected by a receptor called P2RX7 on these T cells, it promptly triggers a self-destruct mechanism. This acts as a built-in kill switch that prevents these powerful immune cells from becoming overactive, causing excessive inflammation, and even damaging bodily tissues.  

The University of Melbourne’s Dr Hui-Fern Koay, an ARC DECRA Fellow at the Doherty Institute and lead of the study, said the research highlights how the body keeps its prompt immune response in check. 

“Unconventional T cells are like the first responders of our immune system—they act fast, but like any rapid action, they need careful regulation,” said Dr Koay. 

“What we found is a negative feedback mechanism that should limit prolonged, unwanted immune responses.” 

Previously hidden immune-cell populations brought to light 

The sensitivity of these cells to NAD and tissue damage has made various T-cell subsets difficult to study in the past. Here, the researchers also discovered a previously overlooked group of unconventional T cells that co-produce two important molecules, interferon-gamma (IFN-g) and interleukin-4 (IL-4), that are key regulators of the immune response.  

These cells are normally lost during laboratory experiments because they self-destruct when exposed to NAD released following tissue damage associated with their isolation. By blocking the P2RX7 receptor, the team was able to preserve and gain new insights into these unchartered immune cell types. 

The University of Melbourne’s Dr Calvin Xu, Research Officer at the Doherty Institute and first author of the study, emphasised the impact of this discovery. 

“Finding these IFN-g and IL-4 dual-producing cells was a significant breakthrough,” said Dr Xu. 

“These cells could help us better understand the diversity of immune functions carried out by unconventional T cells.” 

Unlocking potential new avenues for treatment 

Unconventional T cells are abundant in organs like the liver, where they respond rapidly to signs of infection, inflammation or tissue damage. However, their high sensitivity to damage signals like NAD often leads to premature cell death, limiting their full potential in immune defence. 

Understanding the mechanisms that regulate these cells provides a new target for developing therapies that could either amplify immune responses in diseases like cancer or reduce excessive inflammation in conditions like chronic liver disease. 

By blocking access to the P2RX7 receptor, the researchers were able to improve the survival of these unconventional T cells, suggesting that this approach may offer a strategy for boosting their activity in a range of therapeutic settings.  

The University of Melbourne’s Professor Dale Godfrey, Laboratory Head at the Doherty Institute and co-senior author of the study, noted the potential of this discovery for new treatment strategies. 

“By targeting this regulatory pathway, we may be able to harness the power of these rapid-response cells to improve disease outcomes,” said Professor Godfrey.  

• Peer review: Xu C, et al. Selective regulation of IFN-g and IL-4 co-producing unconventional T cells by purinergic signalling. JEM (2024). DOI: https://doi.org/10.1084/jem.20240354  

• Collaboration: University of Melbourne and University of Queensland 

• Funding: Australian Research Council (ARC), National Health and Medical Research Council (NHMRC).