COVID-19 Immunology: Study Reveals That SARS-CoV-2 Causes CD4 T Cells And CD25 Hyperactivation While Repressing FOXP3 Genes In Severe COVID-19

COVID-19 Immunology: A new study by researchers from Imperial College London-UK and Kumamoto University-Japan has revealed that the SARS-CoV-2 coronavirus causes CD4 T Cells and CD25 hyperactivation while repressing FOXP3 genes in severe COVID-19, causing a T-Cell dysregulation.


 
It has been found that severe COVID-19 patients show various immunological abnormalities including T-cell reduction and cytokine release syndrome, which can be fatal and is a major concern of the pandemic.
 
However, it is poorly understood how T-cell dysregulation can contribute to the pathogenesis of severe COVID-19.
 
In this research, the study team shows the single cell-level mechanisms for T-cell dysregulation in severe COVID-19, demonstrating new pathogenetic mechanisms of T-cell activation and differentiation underlying severe COVID-19.
 
By in silico sorting CD4+ T-cells from a single cell RNA-seq dataset, the study team found that CD4+ T-cells were highly activated and showed unique differentiation pathways in the lung of severe COVID-19 patients. Notably, those T-cells in severe COVID-19 patients highly expressed immunoregulatory receptors and CD25, whilst repressing the expression of FOXP3.
 
Furthermore, the study team showed that CD25+ hyperactivated T-cells differentiate into multiple helper T-cell lineages, showing multifaceted effector T-cells with Th1 and Th2 characteristics. Lastly,
 
The study team lastly showed that CD25-expressing hyperactivated T-cells produces the protease Furin, which facilitates the viral entry of SARS-CoV-2. Collectively, CD4+ T-cells from severe COVID-19 patients are hyperactivated and FOXP3-mediated negative feedback mechanisms are impaired in the lung, which may promote immunopathology.
 
The study findings propose a new model of T-cell hyperactivation and paralysis that drives immunopathology in severe COVID-19.
 
The research findings were published in the peer reviewed journal: Frontiers In Immunology. https://www.frontiersin.org/articles/10.3389/fimmu.2020.589380/full
 
For a while now, there has been speculations among COVID-19 researchers that there is some kind of T cell abnormality in critically ill COVID-19 patients, but specific details have not yet been clarified.
 
To shed light on the problem, the study team performed a genetic analysis of T cells from lung tissue of COVID-19 patients.
 
Their efforts revealed abnormalities in T cells that resulted in overactivation that may cause severe pneumonia. The researchers believe that their findings will lead to new ways of avoiding severe pneumonia caused by coronavirus infections.
 
The COVID-19 pandemic continues to have an enormous impact on daily lives. Why certain individuals become severely ill while the majority of those infected are asymptomatic or very mildly ill is still a major unanswered question. Risk factors for severe disease include old age, diabetes, obesity, and hypertension.
 
To date it is also known that critically ill patients experience an increase in inflammation factors (inflammatory cytokines) and i mmune system overreaction, whereas the number of T cells, the "command centers" for immune cells, is significantly reduced in the blood. However, the medical implications of these findings are still unclear.
 
Typically T cells regulate the activity of the immune system by recognizing specific viruses. They also play important roles in virus elimination and the acquisition of immunity.

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For this research, the study team focused on T cells to determine the causes of severe pneumonia in COVID-19. CD4+ T cells (helper T cells) work to eliminate viruses from the body by promoting the maturation and activation of cytotoxic T cells, which attack virus-infected cells, and B cells, which produce antibodies.
 
However on the other hand, when some CD4+ T cells become highly activated, they express the transcription factor FoxP3 and become regulatory T cells which then act as brakes to inhibit T cell responses.
 
The study team analyzed genetic data from bronchoalveolar lavage fluids from the lungs of patients with COVID-19 from Wuhan, China to characterize the activity and genetic characteristics of the CD4+ T cells present.
 
Utilizing state-of-the-art bioinformatics techniques, the team found that while T cells were markedly activated in the lungs of patients with severe pneumonia, the induction of FoxP3 was inhibited and the T cell braking function stopped working. While T-cell activities are usually balanced between accelerating and braking, one of the most important brakes was not functioning in severe COVID-19 which may have led to severe pneumonia.
 
Differential gene expression analysis showed that in comparison to moderate patients, CD4+ T-cells from severe COVID-19 patients expressed higher levels of the AP-1 genes FOS, FOSB, and JUN, the activation marker MKI67 (Ki67), Th2-related genes IL4R and MAF, and chemokines including CCL2, CCL3, CCL4, CCL7, CCL8, and CXCL8. These suggest that CD4+ T-cells in severe COVID-19 patients are highly activated in the lung, recruiting macrophages, T-cells, and other immune cells. Notably, CD4+ T-cells in severe patients expressed higher levels of immunoregulatory genes including immune checkpoints (CTLA4, HAVCR2 [TIM-3], and LGALS3 [Galectin-3]) as well as the Tregs and T-cell activation marker IL2RA (CD25). These were further confirmed by pathway analysis, which identified interleukin, JAK-STAT, and MAPK signaling pathways as significantly enriched pathways.
 
On the other hand, CD4+ T-cells from severe patients showed decreased expression of interferon-induced genes including IFIT1, IFIT2, IFIT3, and IFITM1. Pathway analysis also showed that CD4+ T-cells from severe patients expressed lower levels of the genes related to interferon downstream pathways suggesting that type-I interferons are suppressed in severe patients. Notably, CD4+ T-cells in severe patients showed lower expression of the TNF superfamily ligands TNFSF10 (TRAIL) and TNFSF14 (LIGHT) and the surface protein SLAMF1 and KLRB1, all of which have roles in viral infections.
https://pubmed.ncbi.nlm.nih.gov/26220166/
 
https://pubmed.ncbi.nlm.nih.gov/15919918/
 
https://pubmed.ncbi.nlm.nih.gov/21920726/
 
https://pubmed.ncbi.nlm.nih.gov/28100610/

Since IL-2 signaling enhances FOXP3 transcription, CD25+ T-cells are likely to differentiate into FOXP3+ Tregs in normal situations. https://pubmed.ncbi.nlm.nih.gov/26215792/
 
However, in severe COVID-19 patients, those CD25+ T-cells are considered to be vigorously proliferating, whilst becoming multifaceted effector T-cells or dying, instead of maturing into FOXP3+ Tregs. Accordingly, the study team  propose ato define the unique activation status of CD25+FOXP3- T-cells as hyperactivated T-cells. CD25 expression occurs mostly in CD4+ T-cells, and therefore, these CD25+ hyperactivated T-cells are likely to be the source of the elevated serum soluble CD25 in severe COVID-19 patients. These hyperactivated CD25+ T-cells produce Furin, which can further enhance SARS-CoV-2 viral entry into pulmonary epithelial cells. Since hyperactivated CD25+ T-cells constitute a rare population, the role of their Furin production, if any, is likely to be limited to their microenvironments. Still, it is possible that, when hyperactivated CD25+ T-cells closely interact with antigen-presenting cells that present viral antigens, their Furin expression may make both antigen presenting cells and themselves more susceptible to the viral infection, which can further dysregulate the T-cell system.
 
CD25+ hyperactivated T-cells also expressed PD-1, and PD-L1 expression in macrophages was increased in severe COVID-19 patients. This clearly shows that the PD-1 system is not able to control hyperactivated T-cells. This may be due to the status of macrophages and other antigen-presenting cells because CD80 on these cells disrupts the PD-1 - PD-L1 interaction and thereby abrogates PD-1-mediated suppression. In addition, PD-L1 expression on lung epithelial cells may play a role in regulating PD-1-expressing T-cells, as shown in other viruses including Influenza Virus and Respiratory Syncytial Virus. https://pubmed.ncbi.nlm.nih.gov/31000591/
 
https://pubmed.ncbi.nlm.nih.gov/24067957/
 
https://pubmed.ncbi.nlm.nih.gov/16388488/
 
Hyperactivated T-cells differentiated into multifaceted Th1-Th2 cells with IL-10 expression. While IL-10 may serve as a growth factor for these cells through their IL-10 receptors, other cytokines in the microenvironment may drive the expression of both Th1 and Th2 transcription factors. Prototypic cytokines for Th1 and Th2 were not differentially expressed in all single cells between moderate and severe patients in the current dataset. Importantly, although T-bet and Gata3 are usually considered as Th1 and Th2 transcription factors, respectively, the expression of both T-bet and Gata3 is induced in CD4⁺ T-cells by TCR signals at the early stage of T-cell activation. This suggests that the multifaceted Th1-Th2 T-cells are in fact still at the early stage of differentiation. Importantly, Foxp3-deficient T-cells show a similar phenotype with multifaceted Th1-Th2 differentiation. Using bacterial artificial chromosome (BAC) Foxp3-GFP reporter and Foxp3-deficient Scurfy mice, Kuczma et al. showed that Foxp3-transcribing T-cells without functional Foxp3 proteins produced both IFN-γ and IL-4.
 
https://www.cell.com/cell/pdf/S0092-8674(09)00899-X.pdf
 
https://pubmed.ncbi.nlm.nih.gov/23408837/
 
https://pubmed.ncbi.nlm.nih.gov/19710455/
 
Despite the biological significance of the multifaceted Th differentiation in severe SARS-CoV-2 infection is not yet clear, the study team suggests that such unfocused T-cell responses will lead to the activation of broad-range of immune cells in an unorganized manner contributing to the hyperactivation as well as paralysis of the immune system in severe COVID-19 patients.
 
Intriguingly, severe COVID-19 patients show elevated levels of serum cytokines such as IL-6, TNF-α, and IL-10, and also increased sCD25 in the serum. https://pubmed.ncbi.nlm.nih.gov/31986264/
 
https://pubmed.ncbi.nlm.nih.gov/32217835/
 
Given that CD25 expression is predominantly found in T-cells, particularly in activated T-cells and Tregs it is likely that significant proportions of T-cells are activated in severe COVID-19 patients and contribute to their ‘cytokine storm’ or CRS. https://pubmed.ncbi.nlm.nih.gov/32022254/
 
Firstly, since cell surface CD25 can be shed from CD25+CD4+ T-cells, CD25+ hyperactivated T-cells may be a significant source of sCD25 in COVID-19 CRS. Secondly, CD25+ hyperactivated T-cells may contribute to the elevation of some of the serum cytokines such as IL-10 in severe COVID-19 patients. https://pubmed.ncbi.nlm.nih.gov/19522766/
 
https://pubmed.ncbi.nlm.nih.gov/31986264/
 
https://pubmed.ncbi.nlm.nih.gov/32217835/
 
Notably, CD25+ hyperactivated T-cells are activated and proliferative, they do not increase in number and also fail to differentiate into Treg as their FOXP3 expression is repressed. These indicate the unique dynamics of activated T-cells in severe COVID-19: a significant proportion of T-cells become activated, proliferate and rapidly die before differentiating into Treg. Such high turn-over of CD25+ hyperactivated T-cells may contribute to immunothrombosis, which is immune-mediated acceleration of thrombosis and is another feature of severe COVID-19. https://pubmed.ncbi.nlm.nih.gov/32835247/
 
Intriguingly, the cancer immunotherapy chimeric antigen receptor T-cell (CAR-T) therapy uses gene-modified activated T-cells as effectors and can induce disseminated intravascular coagulation and immunothrombosis. https://pubmed.ncbi.nlm.nih.gov/31055613/
 
The study findings clarified the association between severe pneumonia and T cell abnormalities. The study team expects that these findings will lead to a better understanding of the mechanisms of severe pneumonia in patients with COVID-19.
 
Dr Masahiro Ono, study Leader and Associate Professor at Kumamoto University told Thailand Medical News, “A more detailed understanding of the pathogenesis based on this research may contribute to the development of drugs to prevent the development of severe COVID-19 and to diagnose the risk of severe disease."
 
In conclusion, the  study  findings demonstrates that SARS-CoV-2 drives hyperactivation of CD4+ T-cells and immune paralysis to promote the pathogenesis of disease and thus life-threatening symptoms in severely affected individuals. Therefore, therapeutic approaches to inhibit T-cell hyperactivation and paralysis may need to be developed for severe COVID-19 patients.
 
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