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Abstract
Regulatory T (Treg) cells orchestrate resolution and repair of acute lung inflammation and injury after viral pneumonia. Compared with younger patients, older individuals experience impaired recovery and worse clinical outcomes after severe viral infections, including influenza and SARS coronavirus 2 (SARS-CoV-2). Whether age is a key determinant of Treg cell prorepair function after lung injury remains unknown. Here, we showed that aging results in a cell-autonomous impairment of reparative Treg cell function after experimental influenza pneumonia. Transcriptional and DNA methylation profiling of sorted Treg cells provided insight into the mechanisms underlying their age-related dysfunction, with Treg cells from aged mice demonstrating both loss of reparative programs and gain of maladaptive programs. Strategies to restore youthful Treg cell functional programs could be leveraged as therapies to improve outcomes among older individuals with severe viral pneumonia.
Highlights
Age is the most important risk factor determining mortality and disease severity in patients infected with influenza virus or SARS coronavirus 2 (SARS-CoV-2; refs. 1–3)
We used heterochronic Treg cell adoptive transfer after influenza infection to establish that the age-related prorepair function of these cells is determined by cell-autonomous mechanisms
The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 represents an unprecedented challenge for the scientific community to identify novel pharmacotherapies and strategies for effective disease management
Summary
Age is the most important risk factor determining mortality and disease severity in patients infected with influenza virus or SARS coronavirus 2 (SARS-CoV-2; refs. 1–3). Age is the most important risk factor determining mortality and disease severity in patients infected with influenza virus or SARS coronavirus 2 Pneumonia related to severe influenza A virus and SARS-CoV-2 infection results in an initial acute exudative phase characterized by release of proinflammatory mediators that damage the alveolar epithelial and capillary barrier to cause refractory hypoxemia and acute respiratory distress syndrome (ARDS) [5]. Immunomodulatory regulatory T (Treg) cells expressing the lineage-specifying transcription factor Foxp dampen inflammatory responses to endogenous and exogenous antigens. Aside from their role in maintaining immune homeostasis through their capacity to suppress overexuberant immune system activation, Treg cells reside in healthy tissues and accumulate in the lung in response to viral injury to promote tissue repair [6,7,8]. Treg cells are capable of promoting tissue regeneration and repair, at least in part through release of reparative mediators, such as the EGF receptor ligand amphiregulin (Areg), which induces cell proliferation and differentiation of the injured tissue [13]
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