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Authors:Benjamin J. Meckiff et al. 

Journal/ Pre-Print:bioRxiv 

Tags: Bioinformatics, Clinical, Immunology/Immunity 

Research Highlights 

  1. SARS-CoV-2-reactive CD4+ T cells display an increase in cytotoxic follicular helper (TFH) and cytotoxic T helper (CD4-CTL) populationswith a decrease in T helper 1 (TH1) and T helper 17 (TH17) populations. 

  1. Cytotoxic TFH frequency is increased in severe patients potentially impairing B cell responses. Similarly, CD4-CTL have higher chemokine expression that may serve to recruit myeloid cells. 

  1. Tregs were reduced in severe patients. 


The researchers conducted an in-depth single-cell RNA sequencing on SARS-CoV-2-reactive CD4+ T cells from COVID-19 patients with different severity and individuals with other respiratory viral exposures (e.g. CoV and flu). The results revealed the expansion of two cell populations, TFH and CD4-CTL in severe COVID patientsat the expense of TH1, TH17 and TREGNotably, with other respiratory viral infections, such as flu, expanded TH1 cells are thought to have a protective effect. Whilst CD4-CTL are also thought to often be associated with a better outcome, the authors suggest that the opposite is the case for COVID, given the abundance of these cells in patients with severe disease.  

Impact for SARS-CoV2/COVID19 research efforts  

  1. Understand the immune response to SARS-CoV2/COVID19  

The research focused on SARS-CoV-2-reactive CD4+ T cells, which provided an insight into the specific response of CD4 T cells in COVID-19 compared to other respiratory viral infections 

  1. Clinical symptoms and pathogenesis of SARS-Cov2/COVID19 

Some of the CD4+ changes may provide insights into pathogenesis and how it related to COVID-related symptoms  

Study Type  

  • In silico study / bioinformatics study 

  • In vitro stimulation with SARS-CoV2 peptide pools  

Strengths and limitations of the paper 

Novelty: Single-cell RNA sequencing was done on virus-reactive CD4+ T cells, a core population involved in adaptive immune response, and possibly, contributing to the hyper-activated inflammatory phenotypes in COVID-19. 

Standing in the field:There have been multiple reports elucidating the role of CD4 T cells reactivity in COVID-19 patients. Many have just focused on identifying the main populations without going into detailed subphenotyping or exploring viral specificity 

Appropriate statistics: They used a reasonable number of patients. 32 COVID-19 patients and 13 healthy controls (other viral infections). They sequenced roughly 100,000 CD4 T cells across patients.  

Viral model used:CD4+ T cells from COVID-19 patients, individuals exposed to other coronavirus, parainfluenza, metapneumovirus and influenza, as well as healthy individuals. 

Translatability:The results provide an understanding of one arm of the immune response, namely CD4 T cells’ contribution to the disease. As it stands it provides more of clinical stratification of patients rather than a direct avenue for intervention without proper understanding for the underlying cause of these phenotypes.  

Main limitations: The research purely described the change of CD4 T cell population in COVID-19 patients compared to other virally-infected or healthy individuals, without validating how these changes are related with the disease. Time of investigation is slightly different for COVID and healthy controls and could account to some of the differences observed in the populations. Flu reactive cells were obtained following vaccination rather than natural viral exposure. Analysis limited to blood and not tissue. Little discussion on the implications of the data