Aging imparts cell-autonomous dysfunction to regulatory T cells during recovery from influenza pneumonia
Luisa Morales-Nebreda, Kathryn A. Helmin, Manuel A. Torres Acosta, Nikolay S. Markov, Jennifer Yuan-Shih Hu, Anthony M. Joudi, Raul Piseaux-Aillon, Hiam Abdala-Valencia, Yuliya Politanska, Benjamin D. Singer
Luisa Morales-Nebreda, Kathryn A. Helmin, Manuel A. Torres Acosta, Nikolay S. Markov, Jennifer Yuan-Shih Hu, Anthony M. Joudi, Raul Piseaux-Aillon, Hiam Abdala-Valencia, Yuliya Politanska, Benjamin D. Singer
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Research Article Aging

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

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.

Authors

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

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Figure 1

Aged mice demonstrate increased mortality and lung inflammation during recovery from influenza infection.

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Aged mice demonstrate increased mortality and lung inflammation during r...
(A) Survival curve comparison of young (2 months, n = 20) and aged (18 months, n = 19) WT mice using log-rank (Mantel-Cox) test. (B) Weight loss percentage from baseline in young (2–4 months, n = 20) and aged (18–22 months, n = 19) mice compared using a mixed-effects model (REML) with Sidak’s post hoc multiple-comparison test. Data presented as mean ± SEM. (C) Representative lung histopathology (H&E staining) of young and aged mice during the naive state and recovery phase after influenza infection (day 60). Original magnification ×10. Scale bar: 500 μm. (D) Flow cytometry quantitative analysis of total number of cells and (E) total number of CD45+ cells from left lung during the naive state and recovery phase from influenza infection. (F) Viral titer measurement of lung homogenates in young and aged mice 14 days after infection. Positive control from influenza A/WSN/33 (H1N1) viral stock. n = 4 mice/group (young — influenza and aged — influenza). Data presented as mean ± SD, 1-way ANOVA with Holm-Sidak’s post hoc testing for multiple comparisons (D and E). *P < 0.05; **P < 0.005; ***P < 0.0005. NS, not significant. n = 4 mice/group (young — naive, aged — naive, young — influenza, and aged — influenza) for D and E.