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Authors:Files et al. 

Journal/ Pre-Print:MedRxiv 

Tags: Immunology/Immunity, Aging, Exhaustion 

Research Highlights

  1. Lymphocyte activation and exhaustion positively correlate with disease severity with highest marker expression in ICU patients and individuals with ongoing SARS-CoV-2 infection 

  1. Within recovered individuals (defined as at least 3-days asymptomatic and 7 days post symptom onset), expression of activation and exhaustion markers increase over time. 

  1. Age is a major determinant of exhaustion phenotypes 


The preprint investigates the question of immune dynamics over the course of SARS-CoV-2 infection. The authors group patients into ongoing (hospitalized group) infections and individuals who remained asymptomatic for at least 3 days (non-hospitalized). They assessed a set of activation and exhaustion markers on various lymphocyte populations. Individuals in the hospitalized groups overall show higher expression of various activation markers (i.e. CD69, Ox40) on T cell and B cell subsets. Further, they correlated the same marker expression in the non-hospitalized group over two blood draws several days apart. They found that Ox40 increases expression, whereas the exhaustion marker PDL1 decreases (though Tim3 increases) on CD4+ T cells. In contrast, CD8+ T cells show an increase of TIGIT and PDL1 expression and a decrease in CD27 memory marker expression over time. The authors find clear correlation of activation, exhaustion, senescence marker expression and the age of the patient, correlating with an immune-aging phenotype. Lastly, the preprint demonstrates that within the hospitalized cohort, cell activation and exhaustion are particularly increased in ICU individuals compared to non-ICU patients.  

Impact for SARS-CoV2/COVID19 research efforts  

Understand the immune response to SARS-CoV2/COVID19  

The preprint characterizes the expression of different exhaustion and activation markers on several lymphoid subsets and find dynamic changes over time and their expression seems to be significantly influenced by patient age.  

Study Type 

  • Clinical Cohort study (e.g. PBMC characterization) 

Strengths and limitations of the paper 

Novelty: Unfortunately, the novelty is rather limited. The paper underlines previous findings of an increased exhaustion and cellular activation phenotype in individuals with ongoing SARS-CoV-2 infection. It further demonstrates that many of the investigated markers strongly depend on the patients age making the contribution of SARS-CoV2 to this phenotype hard to understand. Lastly, but potentially the most significant novel find was that expression of some of the activation and exhaustion marker increased post-recovery. 

Standing in the field:The findings are overall quite confirmatory of previous studies published on T cell exhaustion and activation.  

Appropriate statistics:Overall good use of statistics. 

Viral model used:SARS-CoV-2 infected or convalescent blood from primary patients 

Translatability:The data is rather descriptive, however may help efforts for vaccine  

Main limitations: The grouping of the cohort makes the comparison rather difficult. It remains unclear whether the non-hospitalized group had an overall similar severity when their infection was still ongoing (the discrepancy in age between the cohorts suggest rather not).  

Absolute numbers in Figure 1 would be appreciated to understand the dynamics of the immune cell changes better as proportions will not allow interpretation which specific cell population is changing. 

It would have been good to find age-matched healthy controls to try to control for inflamm-aging related effects on exhaustion and activation phenotypes. It remains unclear whether exhaustion phenotype is exacerbated by SARS-CoV-2 or not. For instance, when correlating age and various activation markers, the expression of the same markers would have been good to establish in an age-matched control cohort. 

The status of the ‘non-hospitalized’ group in terms of SARS-CoV-2 recovery remains unclear. According to the Materials and Methods it is unclear whether the individuals had been tested for seropositivity or qPCR-negativity for SARS-CoV-2. Inclusion criteria are unclear to the reviewer. 

Lastly, the use tetramer and peptide would have improved the study significantly to stain specifically for SARS-CoV-2 reactive T and B cells, respectively. This may give a clearer picture about the antigen-specific immune response and its dynamics during the infection. As it remains unclear whether the changes observed (as taken the bulk of CD4/8 T cells or B cell are changing due to a specific or non-specific response).