Suboptimal SARS-CoV-2-specific CD8+ T-cell response associated with the prominent HLA-A*02:01 phenotype

Journal/preprint name: medrxiv 

Paper DOI: https://www.medrxiv.org/content/10.1101/2020.08.17.20176370v1

Tags:  Cell Biology, Immunology/Immunity, Molecular biology, Virology 

Summary

Habel et al. identified two novel HLA-A*02:01-restricted SARS-CoV-2 epitopes (A2/S269 and A2/Orf1ab3183) in individuals with COVID-19 using a combination of peptide prediction and in vitro peptide stimulation. The authors determined the frequency and activation profiles of the SARS-CoV-2-specific CD8+ T-cell response in acute and convalescent COVID-19 patients and uninfected individuals. The more prominent A2/S269 CD8+ T cell population was equivalent to that seen in acute or convalescent patients positive for HLA-A*02:01. However, although the CD8+ T cell population was higher than in uninfected HLA-A*02:01-positive donors, it was lower compared with the populations that are typically generated in response to other viral epitopes from with influenza (A2/M158) and EBV (A2/BMLF1280) viruses and were negative to activation markers. These data suggest that HLA*02:01 restricted virus-specific CD8+ T were both at low prevalence and express a less than optimal (for virus elimination) phenotype.

Research Highlights  

1. The authors identified two novel HLA-A*02:01-restricted SARS-CoV-2 epitopes (A2/S269 and A2/Orf1ab3183) in individuals with COVID-19  

2. CD8+ T cells which target SARS-CoV-2 presented by the HLA-A802:01 are lower in number than those of other viral infections and are of a phenotype which is suboptimal for viral clearance 

3. Although ‘early memory’ CD8+ T-cells from convalescent HLA-A*02:01 COVID-19 patients were 5-fold higher than those from pre-pandemic samples, the SARS-CoV-2-specific response was 10-fold lower. 

IMPACT FOR COVID-19 RESEARCH:  

Understand the immune response to SARS-CoV2/COVID19  

Although there is a robust CD4+ T Cell response to SARS-CoV-2 infection, the SARS-CoV-2 CD8+ T Cells are suboptimal. This is in line with previous publications by the same research group which found CD4+ T-follicular helper cells and activated CD38+ HLA-DR+ CD8+ T-cells are present in the blood of patients with COVID-19. Although the mechanisms underlying this suboptimal CD8+ T cell response remain unknown, this presents further insight into correlates of protection which currently remain uncertain.  

• Develop a vaccine for SARS-CoV2/COVID19 

• Although this is not the primary aim of the paper, the findings that CD8+ T cells responses in SARS-CoV-2 infected and convalescent patients are suboptimal leads the authors to conclude that an appropriately designed vaccine might elicit a higher protective CD8+ T cell recall response than that which results from a natural infection. 

 Methodologies: 

• Study Type: e.g. in vitro and ex vivo 

• Important cell lines/viral models used: PBMCs from SARS-CoV-2 patients and healthy donors. Viral models were SARS-CoV-2, influenza A and Epstein-Barr virus. 

• Key Techniques: peptide prediction, in vitro peptide stimulation, flow cytometry.  

• Limitations: 

• Further investigation is needed to identify CD8+ T cell epitopes across many HLA class I alleles and SARS-CoV-2 proteins and better determine the CD8+ T-cell responses and their activation profiles in COVID-19. 

• Comparisons of T cell responses would be better in closely related coronaviruses (e.g. SARS-CoV or MERS-CoV). 

• It is uncertain if these results are representative of CD8+ T cells across other HLA class I alleles; however, the authors do acknowledge this limitation and discuss and justify these shortcomings. 

• Figure 4 reports that approximately 70% of CD8+ T cells are positive for intracellular granzyme staining in acute and convalescent COVID-19 patients; this appears unusually high and requires further investigation. The authors do rationalise this by suggesting a bystander effect activation; however, this seems important to clarify, although this may be beyond the scope of this study. 

• It may be helpful to understand whether the HLA-A2 restricted SARS-CoV-2 specific T cell response differs by disease severity.