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23 May 2023

Immune cells with “License to kill” determine severity of COVID-19 in SARS-CoV-2 infection

As the world enters its fourth year of the COVID-19 pandemic, scientists have made a key discovery that could explain why some people get sicker than others with SARS-CoV-2.   

Anti-viral killer T cells (called CD8+ T cells) play a crucial role in our body’s anti-viral defence response. They attack and destroy virus-infected cells, thereby preventing the virus from multiplying and infecting more cells. But to do their job, these CD8+ T cells depend on other cells and molecules to send appropriate combinations of signals to unleash their killing capacity.  

This “license to kill” needs to be carefully regulated. Too strong a response by the killer T cells results in collateral damage that can make the patient sicker. Such overshooting reactions are called ‘immunopathology’ and they are thought to be an important feature in patients that develop severe COVID-19. However, many aspects of why this occurs are still unclear.  

To deepen our knowledge of these processes and to better resolve how the immune system regulates killer T cell responses, scientists from The Peter Doherty Institute for Infection and Immunity (Doherty Institute) and colleagues in Germany at the University of Bonn and Charité University Hospital in Berlin set out to discover how the “licensing” of killer T cells occurs in different viral infections, including COVID-19 

One group of molecules that play an important role in licensing of killer T cells are called Type I interferons. SARS-CoV-2, and other viruses, continuously try to ‘outsmart’ the immune system and often do so by reducing or delaying the production of Type I interferons. How sick a patient becomes from an infection is therefore often also a reflection of this tug-of-war between the immune response and the virus seeking to evade it. 

In a paper published in Nature Immunology, the researchers discovered that another type of T cells, so-called ‘helper T cells’, enables the immune system to still fully activate killer T cell responses, even when the levels of Type I interferons were reduced by the virus.  

The researchers also discovered that such help from other T cells could only compensate for insufficient Type I interferon responses up to a point. Without any Type I interferon, or if its provision is substantially delayed, killer T cells get overactivated. They then contribute to ‘immunopathology’, triggering severe, sometimes even lethal COVID-19.  

Senior author of the study and Laboratory Head at the Doherty Institute, University of Melbourne’s Professor Sammy Bedoui, said the research is a significant breakthrough in our understanding of our how the immune system protects us against virus infections. 

“We discovered that helper T cells allow us to mount optimal killer T cell responses, despite substantial efforts by the virus to prevent this,” Professor Bedoui said.  

“Earlier experimental studies had suggested this might happen, but our study is the first demonstration that this occurs in humans and that these complex mechanisms are linked to disease severity following SARS-CoV-2 infection.” 

First author of the study, Dr Elise Gressier, who conducted this work as part of her PhD studies in the Bonn and Melbourne Research and Graduate School, said that the new insights finally provide long sought-after answers to the unresolved question of why some people get mild, and others severe, COVID-19.  

“Working across the two countries and accessing the research facilities and expertise in both, as part of the joint PhD program in immunology at the Universities of Bonn and Melbourne was key to the success of the study,” Dr Gressier said. 

“This joint research activity occurred despite the complexities brought by COVID-19 travel restrictions and lockdowns.” 

“Our research not only provides a better understanding of why some people get very sick upon SARS-CoV-2 infection, but importantly has identified a number of new potential therapeutic targets that can be exploited for better management of respiratory viruses in the future,” Professor Bedoui concluded. 

Peer review: Nature Immunology

Funding: National Health and Medical Research Council (NHMRC), The Advanced Genomic Collaboration, German Research Council