Yet Another COVID-19 Research, This Time By La Jolla Institute for Immunology Shows That CD4 Cells Are Affected By SARS-CoV-2 Coronavirus
: Scientists from La Jolla Institute for Immunology (LJI), The University of Liverpool and the University of Southampton in a new international study have discovered that the CD4+ cells are affected by the SARS-CoV-2 coronavirus.
The study is the first to give a detailed perspective of how the body's CD4+ T cells respond to the SARS-CoV-2 virus. Among the research findings, it is suggested that early in the illness, patients hospitalized with severe cases of COVID-19 develop a novel T cell subset that can potentially kill B cells and reduce antibody production.
According to the study team the contribution of CD4+ T cells to protective or pathogenic immune responses to SARS-CoV-2 infection to date remains unknown.
In this study involving single-cell transcriptomic analysis of >100,000 viral antigenreactive CD4+ T cells from 40 COVID-19 patients, it was found that in hospitalized patients compared to non-hospitalized patients there were increased proportions of cytotoxic follicular helper (TFH) cells and cytotoxic T helper cells (CD4-CTLs) responding to SARS-CoV-2, and reduced proportion of SARS-CoV-2-reactive regulatory T cells (TREG).
Significantly, in hospitalized COVID-19 patients, a strong cytotoxic TFH response was observed early in the illness which correlated negatively with antibody levels to SARS-CoV-2 spike protein. Polyfunctional T helper (TH)1 and TH17 cell subsets were underrepresented in the repertoire of SARS-CoV-2-reactive CD4+ T cells compared to influenza-reactive CD4+ T cells. Together, the analyses provide insights into the gene expression patterns of SARS-CoV-2-reactive CD4+ T cells in distinct disease severities.
The study findings were in the journal: Cell. https://www.cell.com/cell/pdf/S0092-8674(20)31307-6.pdf?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867420313076%3Fshowall%3Dtrue
The study findings provides a crucial foundation for further detailed analysis and shows the power of a cutting-edge technique called single-cell RNA sequencing (RNA-seq).
LJI Associate Professor Dr Pandurangan Vijayanand, M.D., Ph.D., who led the study with long-time collaborator Dr Christian H Ottensmeier, M.D., Ph.D., FRCP, Professor at the University of Liverpool and adjunct professor at LJI told Thailand Medical news, "This study employs single-cell RNA-seq to analyze RNA molecules expressed by CD4+ T cells that specifically recognize SARS-CoV-2.This lets us show, for the first time, the complete nature of the cells that respond to this virus."
Dr Ottensmeier, a physician scientist who co-led the study added, "This is the beginning. We needed to have a reference to look back at for further studies, and this work is novel, timely, detailed, innovative and open."
Dr Vijayanand and his colleagues at LJI have pioneered the use of single-cell RNA-seq 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.
r this new study, the researchers focused on CD4+ T cells, which play many critical roles in fighting infection.
Study co-first author Dr Benjamin Meckiff, Ph.D., postdoctoral fellow at LJI added, "CD4+ T cells play a central role in orchestrating the immune response. They are a heterogeneous population of immune cells carrying out a wide range of functions, and we have been able to specifically analyze their response to SARS-CoV-2."
Bot Dr Vijayanand and Dr Ottensmeier had planned to use single-cell RNA-seq to analyze CD4+ T cells from patients hospitalized for influenza this year. When the pandemic hit, the researchers applied in early March for approval to use samples from COVID-19 patients as well.
DrVijayanand added, "We were collecting appropriate samples very early on in the pandemic.”
The study team analyzed samples from 40 COVID-19 patients in two groups. The hospitalized group included 22 patients (with nine treated in the ICU). The non-hospitalized group had 18 patients who had experienced milder COVID-19 symptoms.
The researchesr used single-cell RNA-seq to analyze the types of CD4+ T cells that respond to SARS-COV-2 in these patients. Each type of T cell has a role in fighting viruses: some (the "helper" CD4+ T cells) alert the body to infection and recruit other immune cells, while others (TFH cells) signal B cells to make antibodies.
Lastly, some (Tregs) do the important job of inhibiting other T cells, keeping the immune system from damaging the body's own tissues.
Dr Vijayanand added, "There are multiple flavors of T cells that respond to this virus."
The study team cautions that human studies are only correlative and cannot conclude that certain T cell populations are driving disease severity. They do believe some findings warrant a closer look.
For instance, the researchers found that hospitalized patients have higher levels of "cytotoxic" TFH cells, which could potentially make an infection worse. 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 have been seen killing B cells in previous studies.
The study team then examined SARS-CoV-2-specific antibody concentrations in patients. Those with dysfunctional TFH cells also had fewer antibodies.
Dr Meckiff added, "The TFH cells in hospitalized patients displayed gene signatures that suggest they are dysfunctional and aren't giving the help to B cells that we would expect."
The research overall gives the scientific community a starting place to explore CD4+ T cell responses to SARS-CoV-2, and the work establishes a baseline for comparing responses in people over time or with different disease severities.
In order to support these efforts, the researchers made their data immediately available online, just two months after the project began.
Study co-first author Dr Ciro Ramírez-Suástegui, a bioinformatics specialist at LJI added, “We had to be quick. Having the data available for everyone is essential."
Study co-author Dr Vicente Fajardo, an LJI research technician who spearheaded the bioinformatics analysis alongside Ramírez-Suástegui said, "There's definitely more to explore."
Importantly , the data and the research method could be important for more than infectious disease research. Dr Ottensmeier explains that a better understanding of how the body responds to viruses can also guide future research into cancer immunotherapies, which would use the body's own immune system to target and kill cancer cells.
Dr Ottensmeier said,"With this study, we levied our long-standing collaboration for a new human health puzzle. Going forward, we can extend this understanding of what's going on in the blood in response to new viruses to understanding what goes on in the tissue when our immune system deals with cancer."
Dr Ottensmeier and Dr Vijayanand are working on further analysis of COVID-19 patients and also plan to expand their collaboration with the wider University of Liverpool community.
The study team also mentioned, “Another striking observation is the abundance in SARS-CoV-2-reactive CD4+ T cells of CD4-CTLs that express high levels of transcripts encoding for multiple chemokines (XCL1, XCL2, CCL3, CCL4, and CCL5), particularly, from some hospitalized COVID-19 patients. This suggests that the CD4-CTL responses in COVID19 illness may be linked to pathogenesis, although further studies in animal models and large-scale association studies in COVID-19 patients are required to verify or refute this hypothesis. Notably, some hospitalized COVID-19 patients showed impaired TREG response to SARS-CoV-2, and such patients mounted a strong CD4-CTL response, raising another interesting association that warrant testing in larger studies.”
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