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Epitope “megapools” could help determine role T cell immunity plays in COVID-19


Researchers in the United States and Australia have conducted a comprehensive analysis of the epitope recognition patterns associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in humans.

The SARS-CoV-2 virus is responsible for the coronavirus disease 2019 (COVID-19) pandemic that currently has scientists racing to develop effective vaccines and antiviral therapies.

The team – from La Jolla Institute for Immunology (LJI) in California, the University of California San Diego (UCSD), and Murdoch University, Perth –  identified hundreds of human leukocyte antigen (HLA) class I and HLA class II-restricted SARS-CoV-2-derived epitopes. The study revealed distinct patterns of SARS-CoV-2 immunodominance that differed between CD4+ T cells, CD8+ T cells, and antibodies.

Alessandro Sette and colleagues say that to their knowledge, no study to date has described the repertoire of CD4+ and CD8+ T cell SARS-CoV-2 epitopes with a comparable level of granularity or breadth.

The team combined these epitopes to create new epitope “megapools” that can be used to measure virus-specific CD4+ and CD8+ T cell responses and could facilitate research into the role that T cell immunity plays in SARS-CoV-2 infection and COVID-19.

Study: Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases. Image Credit: ktsdesign / Shutterstock

A pre-print version of the paper is available on the bioRxiv* server, while the article undergoes peer review.

T cell responses appear to modulate COVID-19 severity

The disease course following SARS-CoV-2 infection is highly variable, ranging from mild or even asymptomatic, to severe viral pneumonia, respiratory distress and multi-organ damage.

A growing body of evidence points to SARS-CoV-2-specific T cell responses as key modulators of this disease severity. Mild COVID-19 has been associated with coordinated antibody, CD4+ T cell and CD8+ T cell responses, while severe cases have been associated with a lack of coordination in cellular and antibody responses.

To date, most studies aiming to delineate the role that T cell responses play have used pools of predicted or overlapping peptides that span the sequence of different SARS-CoV-2 antigens. However, the exact T cell epitopes and immunodominant antigen regions involved have not been fully determined.

“Defining a comprehensive set of epitope specificities is important for several reasons,” write the researchers.

For example, the ability to determine whether certain regions within different SARS-CoV-2 antigens are immunodominant would be key to ensuring vaccine constructs not only include regions targeted by neutralizing antibodies, but also those capable of delivering sufficient T cell responses.

Furthermore, a comprehensive survey of SARS-CoV-2-derived epitopes restricted by a set of different HLAs that are diverse across the general population would help to ensure study findings are generalizable to different ethnicities.

What did the researchers do?

To identify the pattern of immunodominance across the various SARS-CoV-2 antigens and quantify CD4+ and CD8+ T cell responses to the virus, the team studied epitope-specific T cell responses using  peripheral blood mononuclear cell (PBMC) samples taken from 99 adult convalescent COVID-19 donors.

The SARS-CoV-2 proteome was probed using 1,925 different overlapping peptides that spanned the entire viral genome, to ensure unbiased coverage of the different HLA class II alleles expressed across the study cohort.

For HLA class I, the team selected an additional 5,600 predicted binders for 28 prominent HLA class I alleles, representing 98.8% of HLA class I coverage worldwide.

“We are not aware of any study that describes the repertoire of CD4+ and CD8+ T cell epitopes recognized in SARS-CoV-2 infection with a comparable level of granularity or breadth,” writes the team.

What did they find?

The researchers identified several hundred HLA-restricted SARS-CoV-2-derived epitopes. They observed clear patterns of immunodominance that differed between CD4+ T cells, CD8+ T cells, and antibodies.

A limited number of antigens accounted for around 80% of the total response and overall, the same antigens were dominant for both CD4+ and CD8+ responses.

However, HLA binding capacity was a major determinant of immunogenicity for CD4+ T cells.

“Binding to multiple HLA allelic variants is an important mechanism to amplify the potential immunogenicity of peptide epitopes and specific regions within an antigen,” says Sette and colleagues.

Next, the team projected the CD4+ T cell dominant regions onto known or predicted SARS-CoV-2 protein structures. This revealed that the dominant epitope regions are different for B and T cells.

“This is of relevance for vaccine development, as inclusion of antigen sub-regions selected on the basis of dominance for antibody reactivity might result in an immunogen devoid of sufficient CD4+ T cell activity,” writes the team.

Unlike the clearly distinct dominant regions observed for CD4+ T cell and antibody responses, CD8+ T cell epitopes were distributed uniformly throughout the various antigens, suggesting little positional effect in CD8+ T cell epitope distribution.

“In the case of CD8+ T cell responses, our data highlights HLA-allele specific differences in the frequency and magnitude of responses,” writes the team. “Our study provides a roadmap for inclusion of specific regions or discrete epitopes, to allow for CD8+ T cell epitope representation across a variety of different HLAs.”

Combining the epitopes into megapools

Overall, these experiments identified a total of 280 CD4+ and 454 CD8+ T cell epitopes, which the researchers combined into new epitope megapools to facilitate identification and quantification of SARS-CoV-2-specific CD4+ and CD8+ T cells.

We plan to make these epitope pools available to the scientific community at large, and expect that they will facilitate further investigation of the role of T cell immunity in SARS-CoV-2 infection and COVID-19,” says Sette and colleagues.

The researchers anticipate that the study findings will be of significant value for helping to understand immune responses to SARS-CoV-2 infection and for developing T-cell-based diagnostics.

“In addition, the results shed light on the mechanisms of immunodominance of SARS-CoV-2, which have implications for understanding host-virus interactions, as well as for vaccine design,” they conclude.



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