Abstract:Regulatory T (Treg) cells orchestrate resolution and repair of acute lung inflammation and injury following viral pneumonia. Compared with younger patients, older individuals experience impaired recovery and worse clinical outcomes after severe viral infections, including influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Whether age is a key determinant of Treg cell pro-repair function following lung injury remains unknown. Here, we show that aging results in a cell-autonomous impairm… Show more
“…A recent study by our group found that aged mice exhibited decreased endothelial cell regeneration following influenza infection. We found that this effect was Treg celldependent and Treg cellautonomous, as heterochronic adoptive transfer of young Treg cells into aged mice following influenza viral clearance resulted in a rescue of the aged phenotype compared with an isochronic (age-aligned) adoptive transfer control condition (32). Furthermore, as an ALI progresses, the hyperactive inflammatory response promotes the formation of a hypercoagulable state that drives substantial fibrin deposition and thrombus formation in the lung vasculature (33,34).…”
Section: Acute Lung Injury As a Model System To Dissect Distinct Treg Cell Functionsmentioning
FOXP3 + regulatory T (Treg) cells are a unique subset of CD4 + T cells that classically function as master regulators of immune homeostasis. Besides this canonical suppressive role, which is required to maintain self-tolerance, a growing body of literature has identified Treg cells as critical orchestrators of tissue protection during acute stress and as effector cells that drive repair following tissue injury. Despite substantial interest in these distinct roles, the field has struggled to disentangle Treg cell suppressive functions from those that promote tissue defense and repair. In this article, we will examine the literature in the context of specific physiologic settings, contrasting the suppressive function of Treg cells with their emerging roles in promoting tissue homeostasis and tissue repair. Further, we will discuss a new paradigm differentiating tissue defense from tissue repaira paradigm needed to translate Treg cell-based therapies to the clinic. ImmunoHorizons, 2021, 5: 944-952.
“…A recent study by our group found that aged mice exhibited decreased endothelial cell regeneration following influenza infection. We found that this effect was Treg celldependent and Treg cellautonomous, as heterochronic adoptive transfer of young Treg cells into aged mice following influenza viral clearance resulted in a rescue of the aged phenotype compared with an isochronic (age-aligned) adoptive transfer control condition (32). Furthermore, as an ALI progresses, the hyperactive inflammatory response promotes the formation of a hypercoagulable state that drives substantial fibrin deposition and thrombus formation in the lung vasculature (33,34).…”
Section: Acute Lung Injury As a Model System To Dissect Distinct Treg Cell Functionsmentioning
FOXP3 + regulatory T (Treg) cells are a unique subset of CD4 + T cells that classically function as master regulators of immune homeostasis. Besides this canonical suppressive role, which is required to maintain self-tolerance, a growing body of literature has identified Treg cells as critical orchestrators of tissue protection during acute stress and as effector cells that drive repair following tissue injury. Despite substantial interest in these distinct roles, the field has struggled to disentangle Treg cell suppressive functions from those that promote tissue defense and repair. In this article, we will examine the literature in the context of specific physiologic settings, contrasting the suppressive function of Treg cells with their emerging roles in promoting tissue homeostasis and tissue repair. Further, we will discuss a new paradigm differentiating tissue defense from tissue repaira paradigm needed to translate Treg cell-based therapies to the clinic. ImmunoHorizons, 2021, 5: 944-952.
“…In the mouse models of viral pneumonia, aging can lead to the loss of pro-repair transcriptional programs in Tregs, causing age-related maladaptive T-cell responses, such as effector T-cell differentiation, cell cycle arrest, and DNA damage responses. Aging can also result in the upregulation of the inflammatory responses mediated by Th1 and Th17 cells as well as lung inflammation and injury [ 40 ].…”
Section: Potential Impacts Of Tregs In Covid-19mentioning
The outbreak of coronavirus disease 2019 (COVID-19) is caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which leads to the disruption of immune system, exacerbated inflammation, and even multiple organ dysfunction syndrome. Regulatory T cells (Tregs) are an important subpopulation of T cells that exert immunosuppressive effects. Recent studies have demonstrated that the number of Tregs is significantly reduced in COVID-19 patients, and this reduction may affect COVID-19 patients on several aspects, such as weakening the effect of inflammatory inhibition, causing an imbalance in Treg/Th17 ratio, and increasing the risk of respiratory failure. Treg-targeted therapy may alleviate the symptoms and retard disease progression in COVID-19 patients. This study highlights the recent findings on the involvement of Tregs in the regulation of immune responses to COVID-19, and we hope to provide novel perspectives on the alternative immunotherapeutic strategies for this disease that is currently prevalent worldwide.
“…This is at least in part due to the age-related DNA methylation program, leading to the loss of the reparative transcriptional regulatory network of Treg cells during recovery from influenza-induced lung injury in aged hosts. Moreover, these age-associated Treg cells displayed an inflammatory phenotype characterized by the increased expression of Th1 and Th17 transcription factors and signature cytokines IFN-γ and IL-17 [ 54 ]. Aside from lacking an antigen-receptor, Innate lymphoid cells (ILC) functionally resemble T cells.…”
Section: Age-associated Prolonged Recovery Following Respiratory Viral Infectionmentioning
confidence: 99%
“…Indeed, examination of pathology from lung autopsy samples has revealed extensive evidence of injury and fibrosis that resembled end-stage pulmonary fibrosis in deceased COVID-19 patients [ 66 ], suggesting that severe COVID-19 may cause the development of fibrotic lung diseases. Influenza-induced chronic lung sequelae in young mice are mild and self-limited, while severe persistent inflammatory and fibrotic sequelae were reported in the aged hosts [ 54 , 67 ]. Fig.…”
Section: Aging and The Development Of Pulmonary Sequelae Following Acute Viral Infectionmentioning
confidence: 99%
“…Additionally, post-viral lung fibrosis could involve multiple players aside from CD8 T cells. In this regard, defective Treg function has been linked to the development of age-associated chronic lung conditions following influenza infection [ 54 ]. Notably, Treg function has been shown to limit the profibrotic function of CD4 T RM cells in an allergic model [ 73 ].…”
Section: Aging and The Development Of Pulmonary Sequelae Following Acute Viral Infectionmentioning
The altered immune response in aged hosts play a vital role in contributing to their increased morbidity and mortality during respiratory virus infections. The aged hosts display impaired antiviral immune response as well as increased risk for long-term pulmonary sequelae post virus clearance. However, the underlying cellular and molecular mechanisms driving these alterations of the immune compartment have not been fully elucidated. During the era of COVID-19 pandemic, a better understanding of such aspects is urgently needed to provide insight that will benefit the geriatric patient care in prevention as well as treatment. Here, we review the current knowledge about the unique immune characteristics of aged hosts during homeostasis and respiratory virus infections.
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