Aging imparts cell-autonomous dysfunction to regulatory T cells during recovery from influenza pneumonia

Morales-Nebreda, Luisa; Helmin, Kathryn A.; Torres Acosta, Manuel A.; Markov, Nikolay S.; Hu, Jennifer Yuan-Shih; Joudi, Anthony M.; Piseaux-Aillon, Raul; Abdala-Valencia, Hiam; Politanska, Yuliya; Singer, Benjamin D.

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.