Scientists find high killer T cell response in critical COVID-19 cases

Researchers have found an unusual immune response in unvaccinated, critically ill COVID-19 patients that could inform future vaccines.

A study by teams from the University of Sydney and UNSW, published in the journal Clinical & Translational Immunology, found cytotoxic T cell responses in critical COVID-19 cases were far greater than those in mild or asymptomatic cases.

Cytotoxic T cells – also known as killer T cells or T lymphocytes – are specialised white blood cells that identify and eliminate other malfunctioning or infected cells in the body, including those from viral or bacterial infections, or even cancer.

Sars-cov-2 viruses and immune cell. Conceptual image illustrating antiviral immunity and vaccination.
SARS-CoV-2 viruses and immune cell. Conceptual image illustrating antiviral immunity and vaccination. Credit: Science Photo Library

There are two classes of T cells: Usually, these cells carry CD8 receptors, but some helper T cells, which prime cells to fight off pathogens (rather than killing problems directly) have a CD4 receptor.

The team, led by Professor Jamie Triccas, a microbiologist who is acting deputy director of Sydney University’s Infections Diseases Institute, has found an unusually high number of cytotoxic CD4 cells occur in patients with critical COVID-19 (basically, they’re in ICU) who weren’t vaccinated prior to infection.

Triccas’ team wanted to take an agnostic approach to analysing these samples – waiting to see if there were any associations of particular cell types with disease severity.

When their computer analysis was complete, it was the CD4 cell types that surprised them.

“Most of the time, it’s what we’d call those CD8 T cells that are cytotoxic, and the CD4 type that are the helper [cells]. In this case we see it’s cytotoxic CD4 T cells, which is a little bit unusual,” Triccas tells Cosmos.

“You had this class of T cells that you don’t normally associate with being cytotoxic, that were now having this cytotoxic [characteristic].”

While it’s unusual to see a lymphocyte more commonly known for playing a ‘helper’ role in immune responses suddenly pick up its spear and activate its ‘seek and destroy’ mode, it’s not unheard of.

Previously, cytotoxic CD4s have been seen in patients with viral infections like HIV, Epstein Barr and dengue.

The concern for patients is that a particularly strong immune response could cause excessive tissue damage.

“Those cells, if they’ve been turned on to have a lot of this cytotoxic type ‘killing’ function, the consequence of that could be that you might get some sort of off-target effect,” says Triccas.

“Because these cells are highly activated, they’re making a lot of molecules that activate the immune system and … you get too strong an immune response and you wind up causing excess damage.”

Compare this to patients with more mild and even severe (but not yet critical) cases: their average percentage of more cytotoxic CD4s was markedly lower. In critical cases, they suggest the findings of cytotoxic CD4s in critically ill COVID-19 patients might contribute to tissue damage and systemic inflammation associated with death.

Triccas suggests that while these findings offer little to people at an individual level, they give vaccine manufacturers valuable data when developing next-generation therapies.

“If we want to make new vaccines, or better vaccines, do we have to think about the balance of these types of cells?” he says.

“We know that … generally the goal of the vaccines is to make a lot of antibodies and I don’t think anyone thinks that too many neutralising antibodies is a problem. But I think you can envisage that too many highly active T cells could be a problem.

“Our paper is saying is that you probably should look quite closely at the different types of cells that are made if you’re making a new vaccine, and then decide: am I generating an immune response that’s that is balanced enough to not cause any problems?”

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