16 Apr 2021
Describing the T cell response in COVID-19 patients
Doherty Institute researchers have identified why some people have prominent and long-lasting T cell immune responses during COVID-19, while T cells are of a much smaller magnitude in others.
The team, led by University of Melbourne Professor Katherine Kedzierska, and postdoctoral researchers in her laboratory Dr Oanh Nguyen and Dr Louise Rowntree used specific research tools, called tetramers, to detect killer T cells directly in patients’ blood and subsequently perform in-depth immune analyses.
Killer T cells (CD8+ T cells) are an integral part of mounting an immune response, responsible for finding and destroying infected cells. They recognise virus fragments presented by HLA (human leukocyte antigen) proteins on the outside of infected cells which sparks an immune response.
These virus fragments presented by a known HLA are called “epitopes”. The HLA is a group of proteins that are responsible for the regulation of the immune system and can vary person-to-person.
The research team found that COVID-19 patients expressing a particular HLA, named HLA-B*07:02, elicited robust and numerically superior killer T cell responses when compared to patients expressing other HLA proteins (HLA-A*02:01 and HLA-A*24:02). These prominent killer T cell responses lasted for at least nine months after recovery.
“We found in patients who had been sick with COVID-19 and had recovered, that this particular killer T cell response where the cells were recognising a specific epitope was very strong,” Dr Rowntree said.
“And interestingly, we saw similar killer T cells recognising this epitope in samples from our cohort taken pre-pandemic – so those individuals who haven’t been exposed to COVID-19.”
Dr Nguyen said the killer T cells in pre-pandemic samples are more of a naïve phenotype, whereas the ones seen in the COVID-19 patients have a memory phenotype, or ‘signature’ of a previous immune response.
“There have been hypotheses suggesting cross-reactivity, so the immune system recognising COVID-19 because of previous exposure to coronaviruses, but what we are seeing is that these killer T cells are naïve, they haven’t got that ‘memory signature’ that our cohort who have had COVID-19 show,” Dr Nguyen said.
Published today in Immunity (DOI 10.1016/j.immuni.2021.04.009), the team had access to pre-pandemic samples from children, adults and the elderly, allowing them to do this kind of comparison, which has not been done before.
“We found a very large number of the killer T cells in the pre-pandemic group, so we think having this high number of pre-existing cells is a mechanism for a strong immune response when you do get COVID-19. In the immune response, this killer T cell is certainly one of the strongest in the response,” Dr Nguyen said.
In addition, the team looked at the sequence of the receptor that is on the killer T cells and found that it was extremely diverse.
“So the receptor can be made in a number of different ways, making the epitope we looked at more recognisable, which is why we think it’s so common in people expressing HLA-B*07:02,” Dr Rowntree said.
“It’s sort of like many faces seeing the one thing, whereas other epitopes are only seen by a limited number of faces, we refer to it as plasticity.”
Professor Kedzierska said these exciting findings could help in optimising long-lasting T cell immunity to COVID-19.
“It is of a key importance to provide insight into T cell origins in pre-pandemic samples and their subsequent responses in COVID-19 patients. We can use our findings to better inform next generation COVID-19 vaccine design to elicit broadly-protective immunity,” she concluded.
This research was done in collaboration with Monash University, St Jude Children’s Research Hospital (Memphis, USA), Icahn School of Medicine at Mount Sinai (New York, USA), Austin Hospital, Alfred Hospital, Launceston General Hospital and James Cook University.