COVID-19 Latest Study Shows SARS-CoV-2 Impairs Immune System Including Causing T-Cell Lymphopenia But Increases IL‐10‐Producing Regulatory T Cells

COVID-19 Latest: Scientists and immunologists from the VIB Research Center-Belgium, University of Leuven-Belgium and the The Babraham Institute, Cambridge-UK have in a new study that besides confirming what was already revealed in earlier studies that the SARS-CoV-2 not only impairs the human host immune system and causes T-cell Lymphopenia, has now also discovered that the infection causes an increase in  IL‐10‐Producing Regulatory T Cells that possess anti‐inflammatory properties in the lung and contributes to severe COVID-19.


 
The pandemic spread of the SARS‐CoV‐2 coronavirus is due, in part, to the immunological properties of the host–virus interaction. The clinical presentation varies from individual to individual, with asymptomatic carriers, mild‐to‐moderate‐presenting patients and severely affected patients. Variation in immune response to SARS‐CoV‐2 may underlie this clinical variation.
 
Utilizing a high‐dimensional systems immunology platform, the study team has analyzed the peripheral blood compartment of 6 healthy individuals, 23 mild‐to‐moderate and 20 severe COVID‐19 patients.
 
The team identified distinct immunological signatures in the peripheral blood of the mild‐to‐moderate and severe COVID‐19 patients, including T‐cell lymphopenia, more consistent with peripheral hypo‐ than hyper‐immune activation. Unique to the severe COVID‐19 cases was a large increase in the proportion of IL‐10‐secreting regulatory T cells, a lineage known to possess anti‐inflammatory properties in the lung.
 
As IL‐10‐secreting regulatory T cells are known to possess anti‐inflammatory properties in the lung, their proportional increase could contribute to a more severe COVID‐19 phenotype.
 
The study findings were published in the peer reviewed journal: Clinical & Translational Immunology. https://onlinelibrary.wiley.com/doi/10.1002/cti2.1204
 
The study findings adds to the developing picture of the immune system response and our understanding of the immunological features associated with the development of severe and life-threatening disease following COVID-19.
 
This detailed understanding is crucial to guide the development of effective healthcare and 'early-warning' systems to identify and treat those at risk of a severe response.
 
To date one of the most puzzling questions about the global COVID-19 pandemic is why individuals show such a diverse response. Some individuals do not show any symptoms, termed 'silent spreaders', whereas some COVID-19 patients require intensive care support as their immune response becomes extreme.
 
It is known that age and underlying health conditions are known to increase the risk of a severe response but the underlying reasons for the hyperactive immune response seen in some individuals are unexplained, although likely to be due to many factors contributing together.
 
Innate immune responses are an essential first‐line defense against viruses, including type I and III interferon (IFN). Recent studies have suggested that SARS‐CoV‐2 inhibits type I IFN production and signaling, potentially explaining th e long pre‐symptomatic period and persistent viral load in many patients. https://pubmed.ncbi.nlm.nih.gov/32661059/
 
Defects in NK cell function may also be present, with reports of higher expression of activation and exhaustion markers on NK cells, and impaired NK cytotoxicity and cytokine production, and additional problems with innate immunity are likely to be identified. https://pubmed.ncbi.nlm.nih.gov/32203188/
 
Past studies suggest a defect in the adaptive immune system. Lymphopenia is widely reported in COVID‐19, and the severity of lymphopenia has been correlated with disease severity. https://pubmed.ncbi.nlm.nih.gov/32217835/
 
Functional defects within T cells have been reported, with an increased number of non‐functional CD4+ T cells and impaired T‐cell cytokine production. https://pubmed.ncbi.nlm.nih.gov/32217835/
 
This was confirmed in an independent study, but without significant changes between moderate and severe patients, while another study reported no change. https://pubmed.ncbi.nlm.nih.gov/32161940/
 
Parallel findings were reported in bronchoalveolar lavage fluid of COVID‐19 patients, with enrichment of naïve CD4+ T cells in severely affected patients. https://pubmed.ncbi.nlm.nih.gov/32479746/
 
Overall, it remains to be determined whether defects in innate or adaptive immunity or a synergistic effect of both underlie the unusually long infectious period of SARS‐CoV‐2.
 
Immune analysis is also contributing to an understanding of COVID‐19 pathology. Parallels with other respiratory infections, such as influenza, have led to the hypothesis that pathology is immune‐mediated rather than due to direct viral induction and the potential success of immune‐modulating therapeutics in small‐scale clinical trials provides preliminary support for this model. https://pubmed.ncbi.nlm.nih.gov/25792631/
 
https://pubmed.ncbi.nlm.nih.gov/32501454/
 
https://pubmed.ncbi.nlm.nih.gov/32376398/
 
https://pubmed.ncbi.nlm.nih.gov/32350134/
 
https://pubmed.ncbi.nlm.nih.gov/32376901/
 
Neutrophils seem to be consistently elevated in severe patients and are associated with poor outcomes. https://academic.oup.com/nsr/article/7/6/998/5804736
 
Numerous studies have identified COVID‐19 as a hyper‐inflammatory status, with a ‘cytokine storm’ of pro‐inflammatory cytokines.  Interleukin (IL)‐6, in particular, was consistently higher in severely affected patients compared to moderate and milder cases, suggesting it might be associated with disease severity. https://pubmed.ncbi.nlm.nih.gov/32425950/
 
https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3548761
 
Inconsistent findings have been reported regarding the changes in myeloid subsets; however, severe COVID‐19 patients seem to have an increased number of inflammatory monocytes, producing higher levels of IL‐6 and GM‐CSF. https://www.medrxiv.org/content/10.1101/2020.02.19.20024885v4
 
https://jlb.onlinelibrary.wiley.com/doi/full/10.1002/JLB.4HI0720-470R
 
Bronchoalveolar lavage fluid of severe COVID‐19 cases also revealed high levels of monocytes and neutrophils as well as a pro‐inflammatory environment. https://pubmed.ncbi.nlm.nih.gov/32398875/
 
https://www.sciencedirect.com/science/article/abs/pii/S0092867420305687
 
Excessive T‐cell activation has also been suggested as a possible driver of disease, with increased expression of activation markers (such as HLA‐DR, CD38, CD69, CD25, CD44, Ki‐67, OX40 and CD137) by CD4+ and CD8+ T cells in severe patients. As with the cause of poor viral clearance, the cause of excessive immune pathology remains unclear. https://pubmed.ncbi.nlm.nih.gov/32632085/
 
https://www.medrxiv.org/content/10.1101/2020.03.23.20040675v2
 
In order to investigate the immune system variations that might explain the spectrum of responses, the study team worked with members of the CONTAGIOUS consortium to compare the immune system response to COVID-19 in patients showing mild-moderate or severe effects, using healthy individuals as a control group.
 
Their key motivation for undertaking this research was to understand the complexities of the immune system response occurring in COVID-19 and identify what the hallmarks of severe illness are.
 
Dr Adrian Liston, Professor and Senior Group Leader from Babraham Institute told Thailand Medical News, “The study team believes that the open sharing of data is key to beating this challenge and so established this data set to allow others to probe and analyze the data independently.”
 
The study team specifically looked at the presence of T cells ie immune cells with a diverse set of functions depending on their sub-type, with 'cytotoxic' T cells able to kill virus-infected cells directly, while other 'helper' T cell types modulate the action of other immune cells.
 
The team used flow cytometry to separate out the cells of interest from the participants' blood, based on T cell identification markers, cell activation markers, and cytokine cell signaling molecules.
 
Shockingly, the T cell response in the blood of COVID-19 patients classified as severe showed few differences when compared to healthy volunteers. This is in contrast to what would usually be seen after a viral infection, such as the 'flu.
 
The study team however, identified an increase in T cells producing a suppressor of cell inflammation called interleukin 10 (IL-10). IL-10 production is a hallmark of activated regulatory T cells present in tissues such as the lungs. While rare in healthy individuals, the researchers were able to detect a large increase in the number of these cells in severe COVID-19 patients.
 
Importantly, monitoring the level of IL-10 could provide a warning light of disease progression, but the researchers state that larger-scale studies are required to confirm these findings.
 
Strikingly, COVID‐19 patients that required hospitalization due to their condition harboured a peripheral T‐cell landscape that did not differ substantially from the healthy control one regarding the viral response. This is in stark contrast to the normal phenotype arising with viral infections, which specifically trigger Th1/Tc1‐driven responses, with increased secretion of IFNγ and cytotoxic capacity. This condition has been particularly well studied in the case of influenza which could be considered to date one of the most prevalent respiratory viral infections. https://pubmed.ncbi.nlm.nih.gov/23516986/
 
https://pubmed.ncbi.nlm.nih.gov/29112724/
 
However, patients infected with SARS‐CoV‐2 do not display this distinct Th1/Tc1 polarization. While the mechanism for this polarization failure remains unknown, a potential explanation lies in the presence of a strong IL‐6 environment. IL‐6 is known to affect the Th1/Tc1 response by direct inhibition of IFNγ gene expression.
 
https://pubmed.ncbi.nlm.nih.gov/32416070/

https://pubmed.ncbi.nlm.nih.gov/32407836/
 
https://pubmed.ncbi.nlm.nih.gov/11163196/
 
https://pubmed.ncbi.nlm.nih.gov/27670591/
 
The study results are in line with recent studies regarding the absence of pro‐inflammatory cytokines in the T‐cell compartment or even a decrease of CD4⁺ secreting IFNγ. https://pubmed.ncbi.nlm.nih.gov/32514174/
 
https://pubmed.ncbi.nlm.nih.gov/32514174/
 
These contrasts with data identifying a Th1 signature in COVID‐19 patients; the latter, however, being based on convalescent and non‐hospitalized patients. Intriguingly, IFNγ levels in COVID‐19 patient serum have been reported to be slightly elevated compared to healthy controls.1 If this is not due to differences in the patient cohort, the lack of a Tc1/Th1 phenotype would suggest a myeloid origin as the IFNγ source. https://pubmed.ncbi.nlm.nih.gov/32473127/
 
https://pubmed.ncbi.nlm.nih.gov/32661059/
 
The study was not able to unravel one of the most prominent features of COVID‐19, the prevalent lymphopenia observed in most of the severely affected patients. In the study, both T and B lymphocyte compartments were affected equally, with a possible predominance for CD8⁺ T cells. Importantly, naïve T cells remained present in normal, or elevated, numbers, suggesting that T‐cell production/renewal was intact. Interestingly, this lymphocytopenia seems to be systemic, as previous studies in SARS‐CoV‐1and recently in COVID‐19 patient autopsy revealed a pan‐depletion in all secondary lymphoid organs, including satellite mediastinal lymph nodes with a disrupted architecture (CONTAGIOUS consortium, unpublished data). https://pubmed.ncbi.nlm.nih.gov/17392154/

https://www.medrxiv.org/content/10.1101/2020.03.27.20045427v1

As massive lymphocyte infiltrates are not reported in lung anatomopathological investigations, lymphodepletion is unlikely to be explained by active recruitment of T cells to the lung tissues. An alternative cause of this lymphodepletion would be an increased T‐cell death, either through direct viral cytolysis or increased apoptosis through activation induced cell death (AICD). While lymphopenia may remain an epiphenomenon, the paucity of T cells may equally be contributing to disease. This is tentatively supported by results showing HIV‐positive patients with a slight trend towards poorer COVID‐19 outcome. https://pubmed.ncbi.nlm.nih.gov/32304642/
 
https://pubmed.ncbi.nlm.nih.gov/32304642/
 
https://pubmed.ncbi.nlm.nih.gov/32394344/
 
 In addition, patients who received haematopoietic stem cell transplantation (HSCT), which leads to profound T‐cell lymphopenia, seem to have a worse outcome after SARS‐CoV‐2 infection, since preliminary data suggest 30% mortality according to an ongoing European Society for Blood and Marrow Transplantation survey. https://pubmed.ncbi.nlm.nih.gov/25779951/
 
https://www.medrxiv.org/content/10.1101/2020.05.31.20112979v1
 
The loss of B cells is less likely to contribute to disease, with patients who are genetically depleted of B cells showing normal outcomes. https://pubmed.ncbi.nlm.nih.gov/32333914/
 
https://pubmed.ncbi.nlm.nih.gov/32319118/
 
While the overall T‐cell compartment did not display major differences in comparison with healthy controls, there were two particular enriched T‐cell subsets in more severely affected patients that could reflect the inflammatory condition present in COVID‐19 patients. The inflammatory subset Tc1/Tc17 represents highly activated T cells with high expression of PD‐1 and HLA‐DR in addition to its ability to secrete both IFNγ and IL‐17 cytokines. The presence of this population may reflect a deviation from the normal Tc1 anti‐viral response caused by the pro‐inflammatory IL‐6‐enriched environment. The contribution of this population to the inflammatory setting is, however, debatable, as the increase in relative number is mitigated by the lymphopenia, and no differences were observed between the mild‐to‐moderate and severe COVID‐19 patients. https://pubmed.ncbi.nlm.nih.gov/26206951/
 
The only peripheral biomarker that did delineate disease severity was the increase in IL‐10‐producing regulatory T cells. Elevated IL‐10 has been observed in the serum of COVID‐19 patients before; however, the cellular source was not elucidated. Production of IL‐10 is a hallmark of activated regulatory T cells that reside in tissues such as the lung. This population, normally rare in healthy individuals, rose up to ~ 10% of the regulatory T‐cell pool in severe COVID‐19 patients. The murine analogue to this population has a potent ability to limit inflammation and tissue damage triggered by microbial and environmental interactions at mucosal surfaces. https://pubmed.ncbi.nlm.nih.gov/23667113/
 
In the case of viral infections of the lung, IL‐10 restrains the development of IL‐17‐producing cells that damage the tissue, inhibits the innate inflammatory response to viral particles, and is likely beneficial in reducing the production of cytokines such as IL‐6 that have been implicated in COVID‐19 morbidity.
https://pubmed.ncbi.nlm.nih.gov/21511185/
 
https://pubmed.ncbi.nlm.nih.gov/19494257/
 
https://pubmed.ncbi.nlm.nih.gov/19815506/
 
https://pubmed.ncbi.nlm.nih.gov/32845568/
 
Increase of this suppressive regulatory T‐cell subset could be a direct response to the progressing lung inflammation in COVID‐19 patients, comprising a feedback inhibition circuit to prevent runaway inflammation and death. https://pubmed.ncbi.nlm.nih.gov/28316998/
 
Potentially, elevated IL‐10 could provide a blood‐based biomarker for cases progressing to more severe lung damage. A more intriguing possibility is that individuals with higher IL‐10‐producing regulatory T cells exhibit defective adaptive immunity. IL‐10⁺ regulatory T cells are symptomatic of many unresolved viral infections and are associated with long‐term persistence. In respiratory infections, IL‐10 potently suppresses anti‐viral responses and weakens the immune reaction to super infection with bacteria. https://pubmed.ncbi.nlm.nih.gov/20200252/
 
https://pubmed.ncbi.nlm.nih.gov/27220813/
 
https://pubmed.ncbi.nlm.nih.gov/15187140/
 
Since secondary infection leading to pneumonia is a major cause of death in influenza, and perhaps for some COVID‐19 patients as well, excessive IL‐10 production by regulatory T cells may be a key factor in COVID‐19 outcomes. In principle, this truncated adaptive immune response could allow persistent infection and cause an over‐reliance on innate responses, driving the pathological state. Under this latter model, early intervention (such as with IL‐10 neutralization) could potentially restore appropriate adaptive immunity and quieten the excessively exuberant innate response in the tissue. However, key replication, longitudinal and mechanistic studies would be first required, and IL‐10 has proven stubbornly refractory to immune modulation in the past.
https://pubmed.ncbi.nlm.nih.gov/32835323/
 
https://pubmed.ncbi.nlm.nih.gov/18710327/
 
https://pubmed.ncbi.nlm.nih.gov/32171076/
 
https://pubmed.ncbi.nlm.nih.gov/25481648/
 
Professor Dr Stephanie Humblet-Baron, at the University of Leuven-Belgium added, "We've made progress in identifying the differences between a helpful and harmful immune response in COVID-19 patients. The way forward requires an expanded study, looking at much larger numbers of patients, and also a longitudinal study, following up patients after an illness. This work is already underway, and the data will be available within months."
 
Dr Liston concluded, "This is part of an unprecedented push to understand the immunology of COVID-19. Our understanding of the immunology of this infection has progressed faster than for any other virus in human history and it is making a real difference in treatment. Clinical strategies, such as switching to dexamethasone, have arisen from a better understanding of the immune pathology of the virus, and survival rates are increasing because of it".
 
The study team concluded, “Altogether, our study highlights the absence of a strong anti‐viral response against SARS‐CoV‐2 across mild‐to‐severe COVID‐19 patients and the elevated presence of anti‐inflammatory IL‐10‐producing regulatory T cells in the severely affected patients. These data suggest that a route to normalization of anti‐SARS‐CoV‐2 immunity is critical in the attempt to cure these patients.”

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