T cell anergy in COVID-19 reflects virus persistence and poor outcomes

Journal/preprint name: medRxiv 

Paper DOI: https://doi.org/10.1101/2020.09.21.20198671 

Tags:  Inflammation, Therapeutics, Immunology/Immunity  

Summary  

Hoang et al applied novel approaches to analyse T cell reactivity in 55 COVID-19 patients. T cell activation was measured not only by cytokine production but also by downstream impacts on various cell types. The authors showed that these assays are more sensitive and consistent than classical readouts with PBMCs. Ventilated patients, particularly patients with fatal outcomes, showed lower responses of basophils, pDCs, monocytes and neutrophils to T cell activation and reduced T cell-derived cytokines (IL-3, GM-CSF and IFN-gamma), suggesting an impairment in T cell reactivity in these patients. Gender-specific differences in T cell-induced downstream effects on monocytes were observed. T cell anergy was associated with disease severity and prolonged viral replication. However, impairment in T cell reactivity was reversible in critically ill patients after recovery. Finally, a score was developed based on CD123-upregulation on monocytes, CD11b-upregulation on neutrophils and basophil count to predict fatal outcomes and identify patients who might benefit from strategies to overcome T cell anergy. 

 Research Highlights: 

1. Impaired T cell reactivity (or T cell anergy) is a hallmark of COVID-19 patients and correlates with disease severity  

2. IL-2 partially reversed T cell anergy 

3. Whole blood is superior to PBMCs to quantify T cell anergy in COVID-19 patients 

4. T cell anergy is reversible in critically ill COVID-19 patients after recovery 

5. Basophil counts were markedly reduced in ventilated COVID-19 patients that subsequently died on the ICU 

6. The numbers of pDCs were decreased while the total count of neutrophils was increased in ventilated COVID-19 patients 

7. A combination of three parameters: CD123-upregulation on monocytes, CD11b-upregulation on neutrophils and basophil numbers could predict fatal outcome of patients on mechanical ventilation 

Impact for COVID-19 research:  

• Developing a sensitive approach to measure T cell reactivity in COVID-19 patients.  

• Risk/prognosis estimation 

• Potential target for therapy for critically ill patients 

 Methodologies: 

• Study Type: Clinical immune monitoring  

• Important cell lines/viral models used: SARS-CoV-2-infected patients 

• Key Techniques:  

1. T cell activation assays in whole blood with anti-CD3 antibodies. 

2. Flow cytometry 

3. ELISA 

4. Bioinformatic analysis for predictive score for death in ventilated COVID-19 patients. 

 Limitations: 

• Changes in protein expression on different subsets (including basophils, pDCs, monocytes and neutrophils) were presented as % of control. While the differences can be shown in %, the fold change could be a better representation of the data.  

• T cell activation in PBMC was performed by stimulating T cells with anti-CD3 for 24 hours. It is not clear whether the same effect will be seen in a shorter stimulation (6h). 

• No statistical tests were performed in longitudinal analysis of changes of monocytes and neutrophils, making it hard to predict the significance of the data. 

• The cohort in the study included hospitalised COVID-19 patients. While perhaps outside the scope of the study, it would be interesting to compare T cell anergy in patients with less severe outcomes (i.e asymptomatic patients). 

• T cell activation was measured by TCR stimulation (CD3). Minimal evidence presented for SARS-CoV-2 specific T cell responses.