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

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.

SARS‐CoV‐2, periodontal pathogens, and host factors: The trinity of oral post‐acute sequelae of COVID‐19

“…For example, SARS-CoV-2 open reading frame6 and 8 proteins specifically downregulate MHC-I molecule expression. [298][299][300][301] As stated above, higher inflammation also induces ACE2 expression in inflamed gingiva to provide a conducive microenvironment for virus adherence and entry, 16 ORF3b and ORF6 inhibit IRF3 translocation to the nucleus. [302][303][304] In addition, a reduction in number through autophagy or apoptosis, exhaustion, or anergic may occur if viral infection persists.…”

“…This manifests as a depressed clearance of virus such as SARS‐COV‐2. For example, SARS‐CoV‐2 open reading frame6 and 8 proteins specifically downregulate MHC‐I molecule expression 298–301 . As stated above, higher inflammation also induces ACE2 expression in inflamed gingiva to provide a conducive microenvironment for virus adherence and entry, 16 which in turn, will amplify inflammatory signals.…”

Quality of life at work and fatigue after hospitalization due to COVID‐19

“…For example, a recent German study using diffusion and volumetric magnetic resonance imaging at a median of 7.5 months after the acute phase of COVID‐19, revealed structural changes in thalamus and basal ganglia that were associated with patient‐reported fatigue 27 . Moreover, dysfunction of immune system, especially regulatory T cells, 28 and also autonomic nervous system might play a role in development of long COVID symptoms, including fatigue, after the initial SARS‐CoV‐2 infection. Previous studies revealed that CFS also occurred after other viral infections, caused by herpesviruses or coronaviruses other than SARS‐CoV‐2 29 .…”

The knowns and unknowns of long COVID-19: from mechanisms to therapeutical approaches

“…Tregs, known for their immunosuppressive and immunoregulatory properties, play a significant role in the prognosis of COVID-19. Patients with COVID-19 are reported to have fewer Tregs compared to the general population, leading to diminished inflammatory inhibition and an increased likelihood of respiratory failure and long COVID development ( 128 ). Further, Tregs exert control over both adaptive and innate immune responses through various mechanisms.…”