Scientists in the US and UK are first releasing a detailed look at the battle of CD4 + T cells SARS-CoV-2.
As scientists around the world, lifesaving ones are developing COVID-19 Vaccines and therapies, many still wonder exactly why the disease turns out to be fatal in some people and mild in others.
To solve this mystery, scientists need a thorough understanding of how the body’s many types of immune cells respond to SARS-CoV-2, the virus that causes COVID-19.
A new international study carried out by scientists from the La Jolla Institute of Immunology (LJI), the University of Liverpool and the University of Southampton provides for the first time a detailed snapshot of the reaction of the body’s own CD4 + T cells to SARS-CoV -2 virus. Among the results, their work suggests that patients hospitalized with severe cases of COVID-19 develop a novel T cell subset at the onset of the disease that can potentially kill B cells and reduce antibody production.
The study published on October 6, 2020 in cell, offers a decisive basis for further detailed analyzes – and shows the efficiency of a cutting-edge technology known as a single cell RNA Sequencing (RNA sequence).
Enlarging individual cells
“This study uses single-cell RNA sequence to analyze RNA molecules expressed by CD4 + T cells that specifically recognize SARS-CoV-2,” says LJI Associate Professor Pandurangan Vijayanand, MD, Ph.D ., who led the study for a long time Staff Christian H. Ottensmeier, MD, Ph.D., FRCP, Professor at the University of Liverpool and Associate Professor at the LJI. “In this way, for the first time, we can show the full nature of the cells that respond to this virus.”
“This is the beginning,” says Ottensmeier, a scientist who co-led the study. “We needed a reference to look back on for further study, and this work is novel, contemporary, detailed, innovative and open.”
Vijayanand and his colleagues at LJI pioneered the use of single cell RNA sequences in immunology. RNA-seq gives researchers a new window into the gene expression patterns that can make each person’s immune response to a virus different. For the new study, researchers focused on CD4 + T cells, which play an important role in fighting infections.
“CD4 + T cells play a central role in orchestrating the immune response,” says the study’s first co-author, Benjamin Meckiff, Ph.D., a postdoctoral fellow at the LJI. “They are a heterogeneous population of immune cells that perform a variety of functions, and we were able to specifically analyze their response to SARS-CoV-2.”
Vijayanand and Ottensmeier had planned to use single-cell RNA-seq to analyze CD4 + T cells from patients who were hospitalized for influenza this year. When the pandemic broke out, researchers applied for permission to use samples from COVID-19 patients in early March.
“We collected suitable samples very early in the pandemic,” says Vijayanand.
The researchers examined samples from 40 COVID-19 patients in two groups. The hospitalized group included 22 patients (nine of whom were treated in the intensive care unit). The non-hospitalized group had 18 patients who had milder COVID-19 symptoms.
The scientists used single cell RNA sequence to analyze the types of CD4 + T cells that respond to SARS-COV-2 in these patients. Each T cell type plays a role in fighting viruses: some (the “helper” CD4 + T cells) alert the body to infections and recruit other immune cells, while others (TFH cells) signal B cells to To form antibodies. After all, some (Tregs) take on the important task of inhibiting other T cells and preventing the immune system from damaging the body’s own tissues.
“There are several types of T cells that respond to this virus,” says Vijayanand.
The researchers warn that studies in humans are only correlative and cannot conclude that certain T cell populations affect the severity of the disease. They believe that some results warrant a closer look.
For example, the researchers found that hospital patients have higher levels of “cytotoxic” TFH cells, which could potentially worsen an infection. Instead of doing their job and helping B cells make antibodies, the cytotoxic TFH cells seen in this study were very similar to cells that killed B cells in previous studies. The researchers then examined SARS-CoV-2-specific antibody levels in patients. Those with dysfunctional TFH cells also had fewer antibodies.
“The TFH cells in hospital patients showed gene signatures that suggest they are not working and B cells are not giving the help we would expect,” says Meckiff.
A basis for future research
Overall, the study provides a starting point for the scientific community to examine the responses of CD4 + T cells to SARS-CoV-2, and the work lays a foundation for comparing responses in humans over time or with varying degrees of severity Disease fixed. To support these efforts, the researchers made their data available online immediately two months after the start of the project.
“We had to be quick,” says Ciro Ramírez-Suástegui, co-first author of the study, a bioinformatics specialist at the LJI. “It is important that the data is available to everyone.”
“There’s definitely more to discover,” adds study co-author Vicente Fajardo, an LJI research technician who led bioinformatics analysis alongside Ramírez-Suástegui.
In fact, the data and the research methodology could be important for more than just infectious disease research. Ottensmeier explains that a better understanding of the body’s response to viruses can also guide future research into cancer immunotherapies, which use the body’s immune system to fight and kill cancer cells.
“With this study we have increased our long-term collaboration on a new puzzle for human health,” says Ottensmeier. “In the future, we can expand this understanding of what happens in the blood in response to new viruses to understand what goes on in tissues when our immune system deals with cancer.”
Ottensmeier and Vijayanand are working on further analysis of COVID-19 patients and also plan to expand their collaboration with the wider University of Liverpool community.
Reference: “Imbalance of regulatory and cytotoxic SARS-CoV-2 reactive CD4 + T cells in COVID-19” by Benjamin J. Meckiff, Ciro Ramírez-Suástegui, Vicente Fajardo, Serena J. Chee, Anthony Kusnadi, Hayley Simon and Simon Eschweiler, Alba Grifoni, Emanuela Pelosi, Daniela Weiskopf, Alessandro Sette, Ferhat Ay, Grégory Seumois, Christian H. Ottensmeier and Pandurangan Vijayanand, October 5, 2020, cell.
DOI: 10.1016 / j.cell.2020.10.001
The study, titled “Regulatory and Cytotoxic SARS-CoV-2-Reactive CD4 + T Cells Imbalance in COVID-19” was supported by the National Institutes of Health (Grants U19AI14274, U19AI142742-0S1, U19AI118626, R01HL114093, R35- GM128938). S10RR027366, S10OD025052), the William K. Bowes Jr. Foundation, the Whittaker Foundation, the Wessex Clinical Research Network, and the National Institute of Health Research UK.
Other authors of the study are the co-first author Serena J. Chee, Anthony Kusnadi, Hayley Simon, Simon Eschweiler, Alba Grifoni, Emanuela Pelosi, Daniela Weiskopf, Alessandro Sette, Ferhat Ay and Grégory Seumois.
