SEARCHNARRATIVE_REVIEWimmunology, infectious_disease

narrative_review·immunology, infectious_disease, pulmonology, rheumatology, cardiology·PMC10059134

Regulatory T Cells (Tregs) and COVID-19: Unveiling the Mechanisms, and Therapeutic Potentialities with a Special Focus on Long COVID

Vaccines · 16 authors, 19 centres

AI SUMMARY

FIDELITY 68%

POPULATIONCOVID-19 patients (varying severity, including long COVID), healthy controls, convalescent patients

INTERVENTIONNot applicable (narrative review); discussed interventions include adoptive Treg transfer, low-dose IL-2, CTLA-4-Ig (abatacept), Notch4-DLL4 axis modulation, rapamycin, all-trans retinoic acid, CAR-Treg therapy

COMPARISONComparison of Treg numbers, phenotypes, and functions between COVID-19 patients (mild, severe, critical, long COVID) and healthy controls or convalescent individuals

This summary was generated by AI from a single paper. It has not been reviewed by a clinician and is not clinical advice. Verify against the source before acting on it.

AGENT 01 · STRUCTURED SUMMARY

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TL;DR

Regulatory T cells (Tregs) play a complex, biphasic role in COVID-19: they may suppress antiviral immunity early in infection but are critical for controlling the cytokine storm and tissue damage in severe disease. COVID-19 patients often have reduced Treg numbers and altered Treg phenotypes (e.g., decreased FoxP3 expression), which correlate with disease severity and poor prognosis. Treg dysregulation also persists in long COVID, and Treg-based therapies (e.g., adoptive Treg transfer, low-dose IL-2) show therapeutic potential for managing severe COVID-19 and its sequelae.

Full summary

3,668 CHARS

**Background:** The COVID-19 pandemic, caused by SARS-CoV-2, is characterized by immune dysregulation, hyperinflammation, and acute respiratory distress syndrome (ARDS). Regulatory T cells (Tregs) are a subset of CD4+ T cells with immunosuppressive and immunoregulatory properties, crucial for maintaining immune homeostasis. This review synthesizes current knowledge on the roles of Tregs in COVID-19 pathogenesis, disease severity, long COVID, and their therapeutic potential.

**Methods:** This is a narrative review summarizing findings from multiple studies on Treg biology in COVID-19. The authors discuss data from human cohort studies, single-cell transcriptomic analyses, flow cytometry studies, and animal models. They examine Treg frequency, phenotype (FoxP3, CD25, CTLA-4, PD-1, CD39, CD73, LAG-3), cytokine production (IL-10, TGF-beta, IL-35), and the Treg/Th17 ratio in patients across the spectrum of COVID-19 severity, including long COVID.

**Key Results:** The review highlights conflicting findings regarding Treg dynamics in COVID-19. Several studies report that COVID-19 patients have significantly fewer Tregs than healthy controls, with a reduced Treg/Th17 ratio and lower levels of FoxP3, IL-10, and TGF-beta, particularly in severe cases. For example, one study found that ICU-hospitalized patients had a substantially enhanced Th17/Treg ratio and reduced Treg numbers (Section 3). Another study reported that Tregs (CD3+ CD4+ CD25hi CD127lo FoxP3+) were significantly decreased in severe COVID-19 patients. Conversely, other studies found increased Treg percentages and elevated FoxP3 expression in severe disease, with Tregs exhibiting a unique transcriptional profile similar to tumor-infiltrating Tregs, including upregulation of ENTPD1, LAG3, LRRC32, and pro-inflammatory molecules like IL-32. These perturbations were linked to IL-6 and IL-18 signaling. In long COVID, two studies reported contradictory findings: one found more than two times the number of Tregs in long COVID patients compared to fully recovered subjects, while another recorded a considerable decrease in Treg concentration. A study of over 100 long COVID patients found reduced Treg numbers compared to seronegative controls. Importantly, none of the long COVID studies investigated the immunosuppressive activity of Tregs. The review also notes that Tregs in severe COVID-19 show reduced expression of the master transcription factor FoxP3 and decreased amphiregulin, a tissue-repair mediator.

**Clinical Implications:** The biphasic role of Tregs in COVID-19 suggests that timing and context are critical. Early in infection, Tregs may suppress antiviral CD8+ T-cell responses, potentially worsening outcomes. In later stages, Tregs are essential for controlling hyperinflammation and preventing ARDS. Treg-based therapies are promising: adoptive transfer of allogeneic cord blood-derived Tregs in two severe COVID-19 patients with ARDS led to clinical improvement and reduced proinflammatory cytokines (IL-6, TNF-alpha, IFN-gamma, IL-8, IL-12, MCP-4) without adverse effects. Low-dose IL-2 therapy, which expands Tregs, is being investigated in clinical trials (NCT04724629). Other strategies include CTLA-4-Ig (abatacept), rapamycin, all-trans retinoic acid, and CAR-Treg therapy. The Notch4-DLL4 axis is identified as a potential therapeutic target. The authors emphasize that Treg dysregulation persists in long COVID, but more research is needed to determine whether Treg alterations are causal or correlative. They call for larger studies with standardized Treg characterization methods and investigations into Treg responses following COVID-19 vaccination.

PICO

PPOPULATION

COVID-19 patients (varying severity, including long COVID), healthy controls, convalescent patients

IINTERVENTION

Not applicable (narrative review); discussed interventions include adoptive Treg transfer, low-dose IL-2, CTLA-4-Ig (abatacept), Notch4-DLL4 axis modulation, rapamycin, all-trans retinoic acid, CAR-Treg therapy

OOUTCOME

Treg frequency, FoxP3 expression, Treg/Th17 ratio, cytokine profiles (IL-10, TGF-beta, IL-6, IL-18), disease severity, long COVID symptom persistence

STUDY TYPE

narrative_review

SPECIALTY

immunology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

68% · C

ORIGINAL PAPER

PMC10059134

Regulatory T Cells (Tregs) and COVID-19: Unveiling the Mechanisms, and Therapeutic Potentialities with a Special Focus on Long COVID

Vaccines

READ THE FULL PAPER

ABSTRACT

The COVID-19 pandemic has caused havoc all around the world. The causative agent of COVID-19 is the novel form of the coronavirus (CoV) named SARS-CoV-2, which results in immune system disruption, increased inflammation, and acute respiratory distress syndrome (ARDS). T cells have been important components of the immune system, which decide the fate of the COVID-19 disease. Recent studies have reported an important subset of T cells known as regulatory T cells (Tregs), which possess immunosuppressive and immunoregulatory properties and play a crucial role in the prognosis of COVID-19 disease. Recent studies have shown that COVID-19 patients have considerably fewer Tregs than the general population. Such a decrement may have an impact on COVID-19 patients in a number of ways, including diminishing the effect of inflammatory inhibition, creating an inequality in the Treg/Th17 percentage, and raising the chance of respiratory failure. Having fewer Tregs may enhance the likelihood of long COVID development in addition to contributing to the disease’s poor prognosis. Additionally, tissue-resident Tregs provide tissue repair in addition to immunosuppressive and immunoregulatory activities, which may aid in the recovery of COVID-19 patients. The severity of the illness is also linked to abnormalities in the Tregs’ phenotype, such as reduced expression of FoxP3 and other immunosuppressive cytokines, including IL-10 and TGF-beta. Hence, in this review, we summarize the immunosuppressive mechanisms and their possible roles in the prognosis of COVID-19 disease. Furthermore, the perturbations in Tregs have been associated with disease severity. The roles of Tregs are also explained in the long COVID. This review also discusses the potential therapeutic roles of Tregs in the management of patients with COVID-19.

CITATION EXPORT

Manish Dhawan, Ali A. Rabaan, Sara Alwarthan et al.. Regulatory T Cells (Tregs) and COVID-19: Unveiling the Mechanisms, and Therapeutic Potentialities with a Special Focus on Long COVID. Vaccines. (2023). https://doi.org/10.3390/vaccines11030699

AUTHORS

16 · 19 CENTRES

Manish Dhawan, Ali A. Rabaan, Sara Alwarthan, Mashael Alhajri, Muhammad A. Halwani, Amer Alshengeti, Mustafa A. Najim, Ameen S. S. Alwashmi, Ahmad A. Alshehri, Saleh A. Alshamrani, Bashayer M. AlShehail, Mohammed Garout, Saleh Al-Abdulhadi, Shamsah H. Al-Ahmed, Nanamika Thakur, Geetika Verma

1Department of Microbiology, Punjab Agricultural University, Ludhiana 141004, India
2Trafford College, Altrincham, Manchester WA14 5PQ, UK
3Molecular Diagnostic Laboratory, Johns Hopkins Aramco Healthcare, Dhahran 31311, Saudi Arabia
4College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
5Department of Public Health and Nutrition, The University of Haripur, Haripur 22610, Pakistan
6Department of Internal Medicine, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam 34212, Saudi Arabia
7Department of Medical Microbiology, Faculty of Medicine, Al Baha University, Al Baha 4781, Saudi Arabia
8Department of Pediatrics, College of Medicine, Taibah University, Al-Madinah 41491, Saudi Arabia
9Department of Infection Prevention and Control, Prince Mohammad Bin Abdulaziz Hospital, National Guard Health Affairs, Al-Madinah 41491, Saudi Arabia
10Department of Medical Laboratories Technology, College of Applied Medical Sciences, Taibah University, Al-Madinah 41411, Saudi Arabia
11Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia
12Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Najran University, Najran 61441, Saudi Arabia
13Pharmacy Practice Department, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
14Department of Community Medicine and Health Care for Pilgrims, Faculty of Medicine, Umm Al-Qura University, Makkah 21955, Saudi Arabia
15Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Riyadh 11942, Saudi Arabia
16Dr. Saleh Office for Medical Genetic and Genetic Counseling Services, The House of Expertise, Prince Sattam Bin Abdulaziz University, Dammam 32411, Saudi Arabia
17Specialty Paediatric Medicine, Qatif Central Hospital, Qatif 32654, Saudi Arabia
18University Institute of Biotechnology, Department of Biotechnology, Chandigarh University, Mohali 140413, India
19Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India

EDITOR / REVIEWER

Pedro Plans-Rubió