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Authors:Kusnadi et al.  

Journal/ Pre-Print:Bioarchives 

Tags: Bioinformatics, Clinical, Immunology/Immunity 

Research Highlights

  1. Exhausted SARS-CoV-2 CD8+ T cells from COVID patients upregulate a type I IFN signal signature and a “lack of CD4+ T cell help” transcriptional signature. These cells also present a cytotoxic active signature.  

  1. Common CoV may induce a similar CD8 memory response as pre-pandemic SARS-CoV-2 cross-reactive CD8 share most clusters with SARS-CoV-2 CD8+ T cells from COVID patients, except for one cluster not found in COVID.  

  1. Disease severity segregates SARS-CoV-2-reactive CD8+T cells by exhausted signature (mild COVID) or by non-exhausted and pro-survival signatures (severe COVID), which probably relates to the phase and magnitude of recent stimulation.  

Summary 

Kusnadi et al. analysed virus-reactive CD8 memory T cells from healthy/unexposed, mild and severe COVID by single cell-seqA diversity of CD9+ transcriptional signatures were reported with variation according to virus specificity and state of SARS-COV-2 infection.  SARS-COV-2-specific CD8 from COVID patients were enriched for an exhaustion signature together with strong type I IFN signalling and lack of CD4 help, but presented cytotoxicity. SARS-CoV-2-reactive pre-pandemic samples clustered similarly to those from COVID patients. Exhaustion-like profiles were more pronounced in patients with mild compared with severe disease. Clonal expansion was observed across samples but signatures for severe COVID suggested greater repertoire focussing.  

Impact for SARS-CoV2/COVID19 research efforts  

Understand the immune response to SARS-CoV-2/COVID19  

Study Type  

  • Bioinformatics study from COVID patients’ samples  

Strengths and limitations of the paper 

Novelty: The study highlights the heterogenicity of the SARS-CoV-2 reactive CD8T cellin COVID patients, comparing mild and severe disease and reporting an array of transcriptional signatures. 

Standing in the field: To our knowledge, most published studies regarding CD8+ T cells in COVID-19 relate to an exhaustion phenotype (1-4). Here, differential transcriptomic signatures between severe and mild COVID point to less exhaustion in severe patients. The authors imply that the failure of an exhaustion imprint may correlate to the dysregulation of the T cell response and disease pathogenesis. Also, in line with current literature this may imply that severe COVID may trigger a stronger memory response. 

Appropriate statistics:    Yes 

Viral model used:    Not applicable 

Translatability:    This study does not aim for therapeutics 

Main limitations:  

  • The study focuses on SARS-CoV-2-specific CD8+ T cells based on peptide pools to Spike and Membrane only, while Nucleocapsid has been shown to be important for T cell responses. The analysis is based upon 24h in vitro re-stimulated cells and perhaps an alternative method of isolating specific cells could have been applied (e.g. tetramer). 

  • Severe vs Mild COVID median ages are quite divergent (60 vs 39 yo) and there was no individual follow up to determine any temporal changes in the profile. Low numbers of individuals analysed but in high depth a follow up of some individuals would have been very useful, especially in relation to the speculation about forming different types of memory from severe versus mild disease cases. 

  • The output of the TCR analysis is interesting but the analyses could have been better presented/executed. The numbers of analysed cells will be small in a sc-seq based repertoire and additional higher depth methods should be applied.  

  • Some figures (eg. Extended Fig 2c or Extended Figure 3d) are not well presented