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In view of dysregulated immune response, cytokine storm and inflammation-induced lung damage in severely ill COVID-19 patients, we propose that CD4+CD25+FoxP3+ regulatory T cell-based therapies could be considered for the patient management.
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Potential of regulatory T-cell-based
therapies in the management of severe
To the Editor:
Cytokine storm, inflammation-mediated severe lung damage and defective haemostasis are the main
underlying reasons for morbidity and mortality in coronavirus disease 2019 (COVID-19) patients [1].
Several immunotherapies that target various inflammatory processes have been successfully used in
COVID-19 patients and many other strategies are under evaluation [2, 3]. However, in view of
dysregulated immune responses in severe COVID-19 patients, we suggest that CD4
regulatory T-cell (Treg)-based strategies could be considered for patient management.
Vigorous antimicrobial responses triggered against the pathogen can be detrimental to the host due to
collateral tissue damage. Therefore, regulatory mechanisms, and in particular Tregs, are in place to ensure
that inflammation is kept in check. Tregs are either thymus-derived or induced in the periphery and are
classically known for stimulating immune tolerance, and preventing autoimmune and inflammatory
diseases [4]. Tregs inhibit the activation of both innate and adaptive immune cells via inhibitory surface
molecules (like cytotoxic T-lymphocyte antigen-4 (CTLA-4) and lymphocyte-activation gene-3) and
secretion of immunosuppressive cytokines (interleukin (IL)-10, transforming growth factor-βand IL-35).
Both Treg subsets are equally important to prevent inflammation-induced tissue damage during acute
infections and to promote tissue repair, which is particularly shown in the influenza infection model [4, 5].
The current evidence suggests that the level of peripheral Tregs is prominently reduced in severely ill
COVID-19 patients compared with mild patients [69]. Though the reasons for reduced frequency of
Tregs in peripheral blood are not completely understood, one of the possibilities is that Tregs might have
migrated to the lungs to prevent tissue damage. Detailed investigation of Tregs in the lung tissues of severe
COVID-19 patients and their molecular signatures would provide insight on these questions. However, in
silico analyses performed on the transcriptomic data of CD4
T-cells from the COVID-19 patients
bronchoalveolar lavage suggest that IL2 transcripts were reduced in severe cases compared with mild cases
[10]. Therefore, reduced IL2 would lead to enhanced apoptosis of Tregs and is also confirmed by reduced
levels of FoxP3. Moreover, severe COVID-19 patients have increased levels of soluble IL-2R (CD25) [68],
probably due to inflammation-induced enhanced proteolytic cleavage of cell surface CD25. This soluble
CD25 could potentially interfere with IL-2 bioavailability and signalling, and hence might further promote
apoptosis of Tregs. It has also been shown that Middle East respiratory syndrome coronavirus could infect
T-cells [11] and hence, a direct effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
on the biology of Tregs cannot be ruled out.
Considering the importance of Tregs in immune homeostasis, reduction in the levels of Tregs could be
one of the reasons for the hyperactivated immune system and damaged lungs in severe COVID-19
patients. It is worth noting that depletion of Treg from the mice infected with murine coronavirus lead to
increased mortality with acute encephalitis, thus highlighting the protective nature of Tregs during acute
coronavirus infection [12]. It should also be noted that obesity is one of the risk factors for COVID-19,
and data from obese subjects and pertinent animal models have shown that Tregs in the circulation and
visceral adipose tissues are decreased compared with those in lean subjects, and consequently there is a
higher state of inflammation and insulin resistance [13, 14].
In view of dysregulated immune response, cytokine stormand inflammation-induced lung damage
in severely ill COVID-19 patients, we propose that CD4
regulatory T-cell-based
therapies could be considered for patient management
Cite this article as: Stephen-Victor E, Das M, Karnam A, et al. Potential of regulatory T-cell-based
therapies in the management of severe COVID-19. Eur Respir J 2020; 56: 2002182 [
10.1183/13993003.02182-2020]. Eur Respir J 2020; 56: 2002182
Given the dysregulated immune response in severe COVID-19 patients, we propose that Tregs have
therapeutic potential in patient management. Adoptive transfer of ex vivo expanded polyclonal Tregs has
recently been used to treat autoimmune and inflammatory diseases [15]. But polyclonal Treg therapy is
time consuming, requiring nearly 2 weeks to expand sufficient quantities of viable clinical-grade Tregs for
immunotherapy. However, unlike autoimmune diseases, COVID-19 patients need an instant therapy to
prevent morbidity and mortality. Therefore, adoptive transfer autologous polyclonal Treg therapy is not a
viable option in COVID-19 patients. Also, the approach is not economically feasible for an infectious
disease. Alternatively, allogeneic human leukocyte antigen-matched umbilical cord-derived Tregs are under
exploration for inflammatory conditions (ongoing clinical trials registered at
NCT02932826 and NCT03011021) (figure 1) [16]. In view of the drawbacks of autologous Treg therapy,
allogeneic-matched cord Tregs could be considered for severe COVID-19 patients. Of late, two COVID-19
patients with acute respiratory distress syndrome (ARDS) were treated twice or thrice with allogeneic, off-
the-shelf, cord-blood derived, ex vivo expanded Tregs (1 × 10
cells per dose). The Treg therapy was
associated with rapid decline in the various inflammatory mediators including IL-6, TNF-α, IFN-γ, IL-8
and IL-12 [17].
Another strategy is to boost Tregs in vivo. Low-dose IL-2 has been used to specifically induce Treg
expansion in vivo in type 1 diabetes, and other autoimmune and inflammatory diseases [18]. The high
affinity of CD25 towards IL-2 would lead to selective Treg expansion. But severe COVID-19 patients
display increased levels of soluble IL-2R [68] that could potentially scavenge IL-2. Other reports have
demonstrated that severe COVID-19 patients have increased IL-2 levels [1] and despite having higher IL-2,
Tregs were lower in severe COVID-19 patients. All these arguments suggest that low-dose IL-2 therapy
might not be beneficial in COVID-19 patients. Nevertheless, a clinical trial is planned with low-dose IL-2
for acute respiratory distress syndrome related to COVID-19 (trial NCT04357444 registered at Data from this trial will provide valuable information on the feasibility of this strategy
not only for COVID-19 but also for other acute viral diseases. Other Treg expansion strategies, like IL-2
complexed with monoclonal antibodies to selectively trigger Treg activation [19] or to induce STAT5
phosphorylation and Treg expansion [20], have been explored in pre-clinical models. But they have yet to
be tested in clinic and in view of their unproven efficacy in patients, it is too risky to use them in
COVID-19 patients.
CD25 Allogenic cord blood Treg
Low-dose IL-2 ??
Severe COVID-19 Potential of Treg-based therapeutic strategies in the
management of COVID-19
cell activation,
cell activation,
inflammation CTLA-4-Fc
cell activation,
cell activation,
Treg Treg
FIGURE 1 Potential of regulatory T-cell (Treg)-based therapies in the management of severe coronavirus disease 2019 (COVID-19). Tregs and their
functions are compromised in severe COVID-19 patients, engendering unrestrained immune cell activation. Dysregulated antigen-presenting cells
(APCs) insinuate tissue inflammation and immunopathology by secreting inflammatory cytokines and activating a T-cell-dependent immune
response. We suggest that either adoptive transfer of allogenic Tregs or use of Treg-derived molecules like cytotoxic T-lymphocyte antigen
(CTLA)-4 (abatacept) might block the activation of APC and costimulatory pathways. Such therapies have the potential to curtail tissue
inflammation and immunopathology, leading to better management of COVID-19 patients. IL: interleukin; TNF: tumour necrosis factor. 2
In view of various shortcomings with either adoptive Treg therapy or in vivo Treg expansion strategies,
therapy with Treg-derived immunoregulatory molecules, in particular CTLA-4, might hold the potential
for controlling inflammation in severe COVID-19 patients (figure 1). At cellular level, CTLA-4 interacts
with B7 family members (CD80 and CD86) on innate cells. Through trans-endocytosis and degradation of
B7 molecules inside CTLA-4-expressing cells, CTLA-4 reduces co-stimulatory signals for T-cells [21]. The
recombinant Fc-fused CTLA-4 protein abatacept has been used for several years for the immunotherapy of
systematic autoimmune diseases. Though our knowledge on the mechanisms of this fusion protein is still
incomplete, current literature suggest that by interacting with B7 molecules on antigen-presenting cells,
abatacept interferes with CD28-mediated T-cell signalling and activation [22]. Abatacept might also affect
the activation of innate cells, such as monocytes and dendritic cells, and enhance Tregs, though data on
the Treg function are limited and conflicting [23, 24].
While data is not available regarding abatacept therapy in COVID-19 patients, recent longitudinal
observational studies on the incidence of COVID-19 in abatacept-treated patients provide a pointer towards
its therapeutic potential in severely ill COVID-19 patients. An epidemiological survey performed in the large
tertiary hospital in Barcelona (Spain) indicated that abatacept-treated patients (42 patients from a cohort of
959 patients treated with biological and synthetic disease-modifying anti-rheumatic drugs (DMARD))
exhibited the lowest frequency of COVID-19-compatible symptoms [25]. Similar data were also obtained
from a hospital in Madrid (Spain), where it was noted that none of the 27 abatacept-treated patients (among
802 DMARD-treated patients) were admitted to hospital with COVID-19 symptoms [26]. Furthermore,
among 779 biological DMARD-treated patients from Siena (Italy), only two tested positive for COVID-19
and notably none of the 55 abatacept-treated patients in this cohort experienced COVID-19 [27].
Although these observations are from small cohorts and it is possible that the patients were practicing
strict social distancing, the data on abatacept-treated patients are not surprising in view of its documented
clinical benefits in autoimmune diseases [28] and the mechanisms of action of CTLA-4 to mitigate
inflammatory responses.
Various immunotherapies that target the cytokine storm and prevent lung damage have gained
prominence in the management of severe COVID-19 patients. Among the Treg-based therapeutic
approaches, CTLA-4-based therapies appear to be attractive to overcome the hyperinflammatory state of
severely ill COVID-19 patients. registry shows that 47 studies are registered for the
evaluation of tocilizumab (a humanised monoclonal antibody to IL-6 receptor α)/sarilumab (a fully
human monoclonal antibody to IL-6 receptor α) in COVID-19 patients and 14 studies are registered for
anakinra (an IL-1 receptor antagonist). However, just a single Phase 2 clinical trial has been registered
recently for abatacept therapy in COVID-19 patients (trial NCT04472494 registered at
Initial clinical trials mainly focused on the management of the cytokine storm and in particular, the role
of IL-6 and IL-1β. Data on the Tregs in COVID-19 patients were also scarce during the early period of the
COVID-19 pandemic. These points may explain why abatacept is yet to be considered for the management
of COVID-19 patients, apart from the recently registered clinical trial (NCT04472494). As more data
emerge on the fate of Tregs in COVID-19 patients, the aforementioned clinical observations could be
taken as a basis for initiating randomised trials on CTLA-4-Fc (abatacept) therapy in moderate or severe
COVID-19 patients. Though abatacept therapy in autoimmune patients is not associated with a
predisposition to infection, selection of the dosage and the window of treatment are critical to strike a
balance between inflammation and protective immune response to SARS-CoV-2. We believe that early
treatment with abatacept might not benefit COVID-19 patients as it would curtail effective protective
immune responses against SARS-CoV-2. For the initial exploration, the treatment regimen adapted for the
tocilizumab therapy of COVID-19 patients or even the abatacept regimen used in DMARD treatment of
rheumatic diseases could be considered.
Emmanuel Stephen-Victor
, Mrinmoy Das
, Anupama Karnam
, Bruno Pitard
, Jean-François Gautier
Jagadeesh Bayry
Division of Immunology, Boston Childrens Hospital, Harvard Medical School, Boston, MA, USA.
Institut National de
la Santé et de la Recherche Médicale; Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris,
Paris, France.
Université de Nantes, CNRS ERL6001, Inserm 1232, CRCINA, Nantes, France.
Service de Diabétologie,
Endocrinologie, Nutrition, Centre Universitaire du Diabète et de ses Complications, Hôpital Lariboisière, Université
Paris-Diderot Paris-7, Paris, France.
Correspondence: Jagadeesh Bayry, Institut National de la Santé et de la Recherche Médicale Unité 1138, Centre de
Recherche des Cordeliers, 15 rue de lEcole de Médicine, Paris, F-75006, France. E-mail:
Received: 5 June 2020 | Accepted after revision: 23 June 2020
Conflict of interest: E. Stephen-Victor has nothing to disclose. M. Das has nothing to disclose. A. Karnam has nothing
to disclose. B. Pitard has nothing to disclose. J-F. Gautier has nothing to disclose. J. Bayry reports grants from Agence 3
Nationale de la Recherche, France (Appel Flash COVID-19-COVIMUNE and ANR-19-CE17-0021(BASIN)), outside the
submitted work.
Support statement: Partly supported by grants from Agence Nationale de la Recherche, France (Appel Flash
COVID-19-COVIMUNE and ANR-19-CE17-0021(BASIN)). Funding information for this article has been deposited
with the Crossref Funder Registry.
1Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
Lancet 2020; 395: 497506.
2Lythgoe MP, Middleton P. Ongoing clinical trials for the management of the COVID-19 pandemic. Trends
Pharmacol Sci 2020; 41: 363382.
3Bonam SR, Kaveri SV, Sakuntabhai A, et al. Adjunct immunotherapies for the management of severely ill
COVID-19 patients. Cell Rep Med 2020; 1: 100016.
4Wing JB, Tanaka A, Sakaguchi S. Human FOXP3(+) regulatory T cell heterogeneity and function in
autoimmunity and cancer. Immunity 2019; 50: 302316.
5Arpaia N, Green JA, Moltedo B, et al. A distinct function of regulatory T cells in tissue protection. Cell 2015; 162:
6Qin C, Zhou L, Hu Z, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China.
Clin Infect Dis 2020; 71: 762768.
7Wang F, Hou H, Luo Y, et al. The laboratory tests and host immunity of COVID-19 patients with different
severity of illness. JCI Insight 2020; 5: 137799.
8Chen G, Wu D, Guo W, et al. Clinical and immunological features of severe and moderate coronavirus disease
2019. J Clin Invest 2020; 130: 26202629.
9Wang W, Su B, Pang L, et al. High-dimensional immune profiling by mass cytometry revealed
immunosuppression and dysfunction of immunity in COVID-19 patients. Cell Mol Immunol 2020; 17: 650652.
10 Kalfaoglu B, Almeida-Santos J, Tye CA, et al. T-cell hyperactivation and paralysis in severe COVID-19 infection
revealed by single-cell analysis. bioRxiv 2020; preprint [].
11 Chu H, Zhou J, Wong BH-Y, et al. Middle east respiratory syndrome coronavirus efficiently infects human
primary T lymphocytes and activates the extrinsic and intrinsic apoptosis pathways. J Infect Dis 2016; 213:
12 Anghelina D, Zhao J, Trandem K, et al. Role of regulatory T cells in coronavirus-induced acute encephalitis.
Virology 2009; 385: 358367.
13 Feuerer M, Herrero L, Cipolletta D, et al. Lean, but not obese, fat is enriched for a unique population of
regulatory T cells that affect metabolic parameters. Nat Med 2009; 15: 930939.
14 Wagner N-M, Brandhorst G, Czepluch F, et al. Circulating regulatory t cells are reduced in obesity and may
identify subjects at increased metabolic and cardiovascular risk. Obesity (Silver Spring) 2013; 21: 461468.
15 Bluestone JA, Buckner JH, Fitch M, et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci
Transl Med 2015; 7: 315ra189.
16 Romano M, Fanelli G, Albany CA, et al. Past, present, and future of regulatory T cell therapy in transplantation
and autoimmunity. Front Immunol 2019; 10: 43.
17 Gladstone DE, Kim BS, Mooney K, et al. Regulatory T cells for treating patients with COVID-19 and acute
respiratory distress syndrome: two case reports. Ann Intern Med 2020; in press [DOI: 10.7326/L20-0681].
18 Hartemann A, Bensimon G, Payan CA, et al. Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2
randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2013; 1: 295305.
19 Trotta E, Bessette PH, Silveria SL, et al. A human anti-IL-2 antibody that potentiates regulatory T cells by a
structure-based mechanism. Nat Med 2018; 24: 10051014.
20 Webster KE, Walters S, Kohler RE, et al. In vivo expansion of T reg cells with IL-2mAb complexes: induction of
resistance to EAE and long-term acceptance of islet allografts without immunosuppression. J Exp Med 2009; 206:
21 Qureshi OS, Zheng Y, Nakamura K, et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the
cell-extrinsic function of CTLA-4. Science 2011; 332: 600603.
22 Bonelli M, Scheinecker C. How does abatacept really work in rheumatoid arthritis? Curr Opin Rheumatol 2018;
30: 295300.
23 Bonelli M, Göschl L, Blüml S, et al. Abatacept (CTLA-4Ig) treatment reduces T cell apoptosis and regulatory T
cell suppression in patients with rheumatoid arthritis. Rheumatology (Oxford) 2016; 55: 710720.
24 Langdon K, Haleagrahara N. Regulatory T-cell dynamics with abatacept treatment in rheumatoid arthritis. Int Rev
Immunol 2018; 37: 206214.
25 Michelena X, Borrell H, López-Corbeto M, et al. Incidence of COVID-19 in a cohort of adult and paediatric
patients with rheumatic diseases treated with targeted biologic and synthetic disease-modifying anti-rheumatic
drugs. Semin Arthritis Rheum 2020; 50: 564570.
26 Fernandez-Gutierrez B, Leon L, Madrid A, et al. Hospital admissions in inflammatory rheumatic diseases during
the COVID-19 pandemic: incidence and role of disease modifying agents. medRxiv 2020; preprint [https://10.
27 Conticini E, Bargagli E, Bardelli M, et al. COVID-19 pneumonia in a large cohort of patients treated with
biological and targeted synthetic antirheumatic drugs. Ann Rheum Dis 2020; in press [
28 Genovese MC, Becker JC, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor α
inhibition. N Engl J Med 2005; 353: 11141123.
Copyright ©ERS 2020.
This version is distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. 4
... However, the clinical observation showed that severe and critical patients had higher level of soluble IL-2R, which became a biomarker for early identification of severe COVID-19 and for predicting the clinical progression (106)(107)(108). The increased levels of soluble IL-2R could potentially scavenge IL-2, suggesting low-dose IL-2 therapy was not the optimal regimens for COVID-19 treatment (109). It is reported that an anti-human IL-2 (hIL-2) antibody can increase the Treg/ Teff (effector T cells) ratio when bound to hIL-2 (110). ...
... By increasing trans-endocytosis and degradation of two ligands, CTLA-4 reduces co-stimulatory signals for T-cells (45). The recombinant Fc-fused CTLA-4 protein, Abatacept has been reported to interfere with T-cell signaling and activation, and therefore it has been used for several years for the immunotherapy of many autoimmune diseases (109). Recently, a clinical trial which uses Abatacept in the therapy of COVID-19 patients has been completed ( ...
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Coronavirus disease 2019 (COVID-19) has been raging all around the world since the beginning of 2020, and leads to acute respiratory distress syndrome (ARDS) with strong cytokine storm which contributes to widespread tissue damage and even death in severe patients. Over-activated immune response becomes one of the characteristics of severe COVID-19 patients. Regulatory T cells (Treg) play an essential role in maintaining the immune homeostasis, which restrain excessive inflammation response. So FOXP3 ⁺ Tregs might participate in the suppression of inflammation caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Besides suppressive function, tissue resident Tregs are also responsible for tissue repair. In this review, we mainly summarize the latest research focusing on the change of FOXP3 ⁺ Tregs in the COVID-19 patients, discuss the relationship between disease severity and number change of Tregs and speculate the potential role of FOXP3 ⁺ Tregs during SARS-CoV-2 infection. Furthermore, we introduce some potential Treg-based therapies to improve patients’ outcomes, which include small molecular drugs, antibody drugs, CAR-Treg and cytokine treatment. We hope to reduce tissue damage of severe COVID-19 patients and offer better prognosis through Treg-based therapy.
... Patients with COVID-19 may suffer from an overactive immune system and lung injury due to a reduction of Treg levels. The high frequency of hyperactivated CD25+ T cells may cause immunothrombosis, another symptom of COVID-19 severe manifestations (Kalfaoglu et al., 2020;Stephen-Victor et al., 2020;McGonagle et al., 2020). Another study found that severe COVID-19 patients had a higher number of Tregs with higher levels of FoxP3 expression than mild, recovered, or healthy controls. ...
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An outbreak of coronavirus disease 2019 (COVID-19) emerged in China in December 2019 and spread so rapidly all around the globe. It’s continued and spreading more dangerously in India and Brazil with higher mortality rate. Understanding of the pathophysiology of COVID-19 depends on unraveling of interactional mechanism of SARS-CoV-2 and human immune response. The immune response is a complex process, which can be better understood by understanding the immunological response and pathological mechanisms of COVID-19, which will provide new treatments, increase treatment efficacy, and decrease mortality associated with the disease. In this review we present a amalgamate viewpoint based on the current available knowledge on COVID-19 which includes entry of the virus and multiplication of virus, its pathological effects on the cellular level, immunological reaction, systemic and organ presentation. T cells play a crucial role in controlling and clearing viral infections. Several studies have now shown that the severity of the COVID-19 disease is inversely correlated with the magnitude of the T cell response. Understanding SARS-CoV-2 T cell responses is of high interest because T cells are attractive vaccine targets and could help reduce COVID-19 severity. Even though there is a significant amount of literature regarding SARS-CoV-2, there are still very few studies focused on understanding the T cell response to this novel virus. Nevertheless, a majority of these studies focused on peripheral blood CD4+ and CD8+ T cells that were specific for viruses. The focus of this review is on different subtypes of T cell responses in COVID-19 patients, Th17, follicular helper T (TFH), regulatory T (Treg) cells, and less classical, invariant T cell populations, such as δγ T cells and mucosal-associated invariant T (MAIT) cells etc that could influence disease outcome.
... Importantly, this tissue protective effect is independent of the immune suppressive function of Tregs and their classical regulatory role (12). In addition, Tregs have been addressed in the context of SARS-CoV-2 infection and several studies revealed that in patients with severe COVID-19, marked by potent cytokine storm, Tregs might be beneficial for the lung environment, dampening the pro-inflammatory cues and restoring tissue integrity (88) (Figure 3). On the other hand, excessive immune regulation by Tregs may hamper an effective immune response against SARS-CoV-2 and thereby exacerbate disease severity (89). ...
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Regulatory T cells (Tregs) restrain excessive immune responses and dampen inflammation. In addition to this classical immune suppressive role, Tregs in non-lymphoid tissues also promote tissue homeostasis, regeneration and repair. In this review, we outline our current understanding of how Tregs migrate to peripheral tissues and the factors required for their maintenance at these sites. We discuss the tissue-specific adaptations of Tregs at barrier and immuno-privileged sites and the mechanisms that regulate their function within these organs. Furthermore, we outline what is known about the interactions of Tregs with non-immune cells in the different peripheral tissues at steady state and upon challenge or tissue damage. A thorough understanding of the tissue-specific adaptations and functions of Tregs will potentially pave the way for therapeutic approaches targeting their regenerative role.
... Additionally, abatacept (recombinant Fc-fused CTLA-4 protein) could potentially influence innate cell activation, such as monocytes and dendritic cells, and increase Tregs, although research on Treg activity is limited and contradictory [116,120]. Moreover, abatacept could be an attractive drug to reduce the hyperinflammation condition of severe COVID-19 patients [121]. ...
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Coronavirus disease 2019 (COVID-19) has been raised as a pandemic disease since December 2019. Immunosuppressive cells including T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs) are key players in immunological tolerance and immunoregulation; however, they contribute to the pathogenesis of different diseases including infections. Tregs have been shown to impair the protective role of CD8+ T lymphocytes against viral infections. In COVID-19 patients, most studies reported reduction, while few other studies found elevation in Treg levels. Moreover, Tregs have a dual role, depending on the different stages of COVID-19 disease. At early stages of COVID-19, Tregs have a critical role in decreasing antiviral immune responses, and consequently reducing the viral clearance. On the other side, during late stages, Tregs reduce inflammationinduced organ damage. Therefore, inhibition of Tregs in early stages and their expansion in late stages have potentials to improve clinical outcomes. In viral infections, MDSC levels are highly increased, and they have the potential to suppress T cell proliferation and reduce viral clearance. Some subsets of MDSCs are expanded in the blood of COVID-19 patients; however, there is a controversy whether this expansion has pathogenic or protective effects in COVID-19 patients. In conclusion, further studies are required to investigate the role and function of immunosuppressive cells and their potentials as prognostic biomarkers and therapeutic targets in COVID-19 patients.
... Cytotoxic T lymphocyte-associated antigen (CTLA-4) works by suppression of T-cell stimulatory signals (47)(48)(49). It binds both B7 family members (B7-1 and B7-2) with considerably higher affinity than CD28 (50). ...
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Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2. During T-cell activation, the immune system uses different checkpoint pathways to maintain co�inhibitory and co-stimulatory signals. In COVID-19, expression of immune checkpoints (ICs) is one of the most important manifestations, in addition to lymphopenia and inflammatory cytokines, contributing to worse clinical outcomes. There is a controversy whether upregulation of ICs in COVID-19 patients might lead to T-cell exhaustion or activation. This review summarizes the available studies that investigated IC receptors and ligands in COVID-19 patients, as well as their effect on T-cell function. Several IC receptors and ligands, including CTLA-4, BTLA, TIM-3, VISTA, LAG-3, TIGIT, PD-1, CD160, 2B4, NKG2A, Galectin-9, Galectin-3, PD-L1, PD-L2, LSECtin, and CD112, were upregulated in COVID-19 patients. Based on the available studies, there is a possible relationship between disease severity and increased expression of IC receptors and ligands. Overall, the upregulation of some ICs could be used as a prognostic biomarker for disease severity
... Cytotoxic T lymphocyte-associated antigen (CTLA-4) works by suppression of T-cell stimulatory signals (47)(48)(49). It binds both B7 family members (B7-1 and B7-2) with considerably higher affinity than CD28 (50). ...
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Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2. During T-cell activation, the immune system uses different checkpoint pathways to maintain coinhibitory and co-stimulatory signals. In COVID-19, expression of immune checkpoints (ICs) is one of the most important manifestations, in addition to lymphopenia and inflammatory cytokines, contributing to worse clinical outcomes. There is a controversy whether upregulation of ICs in COVID-19 patients might lead to T-cell exhaustion or activation. This review summarizes the available studies that investigated IC receptors and ligands in COVID-19 patients, as well as their effect on T-cell function. Several IC receptors and ligands, including CTLA-4, BTLA, TIM-3, VISTA, LAG-3, TIGIT, PD-1, CD160, 2B4, NKG2A, Galectin-9, Galectin-3, PD-L1, PD-L2, LSECtin, and CD112, were upregulated in COVID-19 patients. Based on the available studies, there is a possible relationship between disease severity and increased expression of IC receptors and ligands. Overall, the upregulation of some ICs could be used as a prognostic biomarker for disease severity.
... There are some studies that strongly suggest the formation of immunological memory of T cells following improvement from SARS-CoV-2. This evidence highlights the important role of T cells in the diagnosis and treatment of severe patients 95 . ...
Coronaviruses (CoVs) are a group of very diverse viruses that cause a broad spectrum of diseases from mild to severe enteric, respiratory, systemic diseases, and common cold or pneumonia among humans and animals. This virus is associated with Middle East Respiratory Syndrome (MERS), Severe Acute Respiratory Syndrome (SARS), and lung disease that lead to Acute Respiratory Distress Syndrome (ARDS). In December 2019, researchers identified a novel coronavirus type, called Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2), which was associated with symptoms of high fever, dry cough, headache, diarrhea, and reduction of White Blood Cells (WBC). Coronavirus-associated acute respiratory disease was named Coronavirus Disease 19 (COVID-19). No proven treatment has been discovered for COVID-19 so far, but researchers are trying to find the best effective way to treat this disease. Therefore, therapeutic strategies that facilitate the recovery of COVID-19 patients and reduce life-threatening complications are urgently needed now. Today, Mesenchymal Stem Cells (MSCs) and their secretion are utilized as one of the most applied tools to treat various diseases such as inflammation and cancer. MSC-derived vesicles are rich in various growth factors, cytokines, and interleukins that are produced and secreted under different physiological or pathological conditions. These vesicles were considered a suitable and effective tool in regeneration medicine because of their high power in repairing damaged tissues and modulating immune responses. Recently, evidence has shown MSC-derived vesicles through reduced expression of pro-inflammatory cytokines could improve damaged tissues in COVID-19 patients. In addition to MSCs and MSC-derived exosomes, Natural Killer (NK) cells, T cells, and platelet lysates were used against viral infection. In this review, we tried to provide an overview of MSC secretion and immune cells for COVID-19 therapy.
... This grants importance to interventions with antiinflammatory properties, which is the case for RT [116][117][118]. It is also important to note that regulatory T lymphocyte (Treg) is associated with controlling inflammatory response and is reduced in severely ill patients [119,120], suggesting its important role in COVID-19 progression. In this regard, a previous study showed that RT can upregulate Treg [121] and that the regular practice of RT increases the levels of interleukin-10, an anti-inflammatory cytokine that is mainly produced by Treg cells [117,118]. ...
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By the end of 2019 a severe acute respiratory syndrome caused by the SARS-CoV-2 started a pandemic, leading to millions of deaths and many important political and social changes. Even in the absence of contamination, the mobility reduction, social distancing and closing of exercise facilities negatively affected physical activity and conditioning, which is associated to muscle atrophy, loss of muscle strength and reductions in functional capacity. In case of infection, it has been shown that increased physical capacity is associated with decreased hospitalization and mortality risk. Although millions of people died from COVID-19, most contaminated individu-als survived from the infection, but carried different sequelae, like severe loss of physical func-tion and reduced quality of life. Among different physical exercise models that might help to prevent and treat COVID-19 outcomes, resistance training (RT) might be particularly relevant. Among its benefits, RT can be adapted to be performed in many different situations, even with limited space and equipment, and it is easily adapted to individual characteristics and health status. The current narrative review aims to provide insights on how RT can be used in different scenarios to counteract the negative effects of COVID-19. By this, the authors expect to provide insights do deal with the current pandemic and also in case the World has to deal with similar events in the future.
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In the last century, we have seen a dramatic rise in the number of older persons globally, a trend known as the grey (or silver) tsunami. People live markedly longer than their predecessors worldwide, due to remarkable changes in their lifestyle and in progresses made by modern medicine. However, the older we become, the more susceptible we are to a series of age-related pathologies, including infections, cancers, autoimmune diseases, and multi-morbidities. Therefore, a key challenge for our modern societies is how to cope with this fragile portion of the population, so that everybody could have the opportunity to live a long and healthy life. From a holistic point of view, aging results from the progressive decline of various systems. Among them, the distinctive age-dependent changes in the immune system contribute to the enhanced frailty of the elderly. One of these affects a population of lymphocytes, known as regulatory T cells (Tregs), as accumulating evidence suggest that there is a significant increase in the frequency of these cells in secondary lymphoid organs (SLOs) of aged animals. Although there are still discrepancies in the literature about modifications to their functional properties during aging, mounting evidence suggests a detrimental role for Tregs in the elderly in the context of bacterial and viral infections by suppressing immune responses against non-self-antigens. Interestingly, Tregs seem to also contribute to the reduced effectiveness of immunizations against many pathogens by limiting the production of vaccine-induced protective antibodies. In this review, we will analyze the current state of understandings about the role of Tregs in acute and chronic infections as well as in vaccination response in both humans and mice. Lastly, we provide an overview of current strategies for Treg modulation with potential future applications to improve the effectiveness of vaccines in older individuals.
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Severe COVID-19 patients can show respiratory failure, T-cell reduction, and cytokine release syndrome (CRS), which can be fatal in both young and aged patients and is a major concern of the pandemic. However, the pathogenetic mechanisms of CRS in COVID-19 are poorly understood. Here we show single cell-level mechanisms for T-cell dysregulation in severe SARS-CoV-2 infection, and thereby demonstrate the mechanisms underlying T-cell hyperactivation and paralysis in severe COVID-19 patients. By in silico sorting CD4+ T-cells from a single cell RNA-seq dataset, we 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 the transcription factor FOXP3 and interestingly, both the differentiation of regulatory T-cells (Treg) and Th17 was inhibited. Meanwhile, highly activated CD4+ T-cells express PD-1 alongside macrophages that express PD-1 ligands in severe patients, suggesting that PD-1-mediated immunoregulation was partially operating. Furthermore, we show that CD25+ hyperactivated T-cells differentiate into multiple helper T-cell lineages, showing multifaceted effector T-cells with Th1 and Th2 characteristics. Lastly, we show that CD4+ T-cells, particularly CD25-expressing hyperactivated T-cells, produce 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, while activated CD4+ T-cells continue to promote further viral infection through the production of Furin. Therefore, our study proposes a new model of T-cell hyperactivation and paralysis that drives pulmonary damage, systemic CRS and organ failure in severe COVID-19 patients.
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Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has infected millions with more than 181,000 fatal cases as of 22nd April 2020. Currently, there are no specific COVID-19 therapies. Most patients depend on mechanical ventilation. Current COVID-19 data clearly highlight that cytokine storm and activated immune cell migration to the lungs characterize the early immune response to COVID-19 that causes severe lung damage and development of acute respiratory distress syndrome. In view of uncertainty associated with immunosuppressive treatments such as corticosteroids and their possible secondary effects, including risks of secondary infections, we suggest immunotherapies as an adjunct therapy in severe COVID-19 cases. Such immunotherapies based on inflammatory cytokine neutralization, immunomodulation and passive viral neutralization, not only reduce inflammation, inflammation-associated lung damage, or viral load, but could also prevent intensive care unit hospitalization and dependency on mechanical ventilation both of which are limited resources.
Regulatory T (Treg) cells expressing the transcription factor Foxp3 have a critical role in the maintenance of immune homeostasis and prevention of autoimmunity. Recent advances in single cell analyses have revealed a range of Treg cell activation and differentiation states in different human pathologies. Here we review recent progress in the understanding of human Treg cell heterogeneity and function. We discuss these findings within the context of concepts in Treg cell development and function derived from preclinical models and insight from approaches targeting Treg cells in clinical settings. Distinguishing functional Treg cells from other T cells and understanding the context-dependent function(s) of different Treg subsets will be crucial to the development of strategies toward the selective therapeutic manipulation of Treg cells in autoimmunity and cancer.
Background: In this pandemia, it is essential for rheumatologist and patients to know the relationship between COVID-19 and inflammatory rheumatic diseases (IRD). We want to assess the role of targeted synthetic or biologic disease modifying antirheumatic drugs (ts/bDMARDs) and other variables in the development of moderate-severe COVID-19 disease in IRD. Methods: An observational longitudinal study was conducted (1stMar to 15thApr 2020). All patients from the rheumatology outpatient clinic from a hospital in Madrid with a medical diagnosis of IRD were included. Main outcome: hospital admission related to COVID-19. Independent variable: ts/bDMARDs. Covariates: sociodemographic, comorbidities, type of IRD diagnosis, glucocorticoids, NSAIDs and conventional synthetic DMARDs (csDMARDs). Incidence rate (IR) of hospital admission related to COVID-19, was expressed per 1,000 patients-month. Cox multivariate regression analysis was run to examine the influence of ts/bDMARDs and other covariates on IR. Results: 3,591 IRD patients were included (5,896 patients-month). Concerning csDMARDs, methotrexate was the most used followed by antimalarials. 802 patients were on ts/bDMARDs, mainly anti-TNF agents, and rituximab. Hospital admissions related to COVID-19 occurred in 54 patients (1.36%) with an IR of 9.15 [95%CI: 7-11.9]. In the multivariate analysis, older, male gender, presence of comorbidities and specific systemic autoimmune conditions (Sjoegren, polychondritis, Raynaud and mixed connective tissue disease) had more risk of hospital admissions regardless other factors. Exposition to ts/bDMARDs did not achieve statistical signification. Use of glucocorticoids, NSAIDs, and csDMARDs dropped from the final model. Conclusion: This study provides additional evidence in IRD patients regarding susceptibility to moderate-severe infection related to COVID-19.
OBJECTIVES To investigate the incidence of COVID-19 in a cohort of adult and paediatric patients with rheumatic diseases receiving targeted biologic and synthetic disease modifying anti-rheumatic drugs (tDMARDs) and to explore the possible effect of these treatments in the clinical expression of COVID-19. METHODS A cross-sectional study comprising of a telephone survey and electronic health records review was performed including all adult and paediatric patients with rheumatic diseases treated with tDMARDs in a large rheumatology tertiary centre in Barcelona, Spain. Demographics, disease activity, COVID-19 related symptoms and contact history data were obtained from the start of the 2020 pandemic. Cumulative incidence of confirmed cases (SARS-CoV-2 positive PCR test) was compared to the population estimates for the same city districts from a governmental COVID-19 health database. Suspected cases were defined following WHO criteria and compared to those without compatible symptoms. RESULTS 959 patients with rheumatic diseases treated with tDMARDs were included. We identified 11 confirmed SARS-CoV-2 positive cases in the adult cohort and no confirmed positive cases in the paediatric cohort. COVID-19 incidence rates of the rheumatic patient cohort were very similar to that of the general population [(0.48% (95% CI 0.09 to 8.65%)] and [0.58% (95% CI 5.62 to 5.99%)], respectively. We found significant differences in tDMARDs proportions between the suspected and non-suspected cases (p=0.002). CONCLUSION Adult and paediatric patients with rheumatic diseases on tDMARDs do not seem to present a higher risk of COVID-19 or a more severe disease outcome when compared to general population.
Background: The Coronavirus Disease-2019 (COVID-19), infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a severe outbreak in China. The host immunity of COVID-19 patients is unknown. Methods: The routine laboratory tests and host immunity in COVID-19 patients with different severity of illness were compared after patient admission. Results: A total of 65 SARS-CoV-2-positive patients were classified as mild (n=30), severe (n=20), and extremely severe (n=15) illness. Many routine laboratory tests such as ferritin, lactate dehydrogenase and D-dimer were increased in severe and extremely severe patients. The absolute numbers of CD4+ T cells, CD8+ T cells and B cells were all gradually decreased with increased severity of illness. The activation markers such as HLA-DR and CD45RO expressed on CD4+ and CD8+ T cells were increased in severe and extremely severe patients compared with mild patients. The co-stimulatory molecule CD28 had opposite results. The percentage of natural regulatory T cells was decreased in extremely severe patients. The percentage of IFN-γ producing CD8+ T cells was increased in both severe and extremely severe patients compared with mild patients. The percentage of IFN-γ producing CD4+ T cells was increased in extremely severe patients. The IL-2R, IL-6, and IL-10 were all increased in extremely severe patients. The activation of DC and B cells was decreased in extremely severe patients. Conclusions: The number and function of T cells are inconsistent in COVID-19 patients. The hyperfunction of CD4+ and CD8+ T cells is associated with the pathogenesis of extremely severe SARS-CoV-2 infection.
COVID-19 has rapidly developed into a worldwide pandemic with a significant health and economic burden. There are currently no approved treatments or preventative therapeutic strategies. Hundreds of clinical studies have been registered with the intention of discovering effective treatments. Here, we review currently registered interventional clinical trials for the treatment and prevention of COVID-19 to provide an overall summary and insight into the global response.