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 7

Aged lung Treg cells fail to upregulate a prorepair transcriptional program to the same extent as young Treg cells during recovery from influenza infection.

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Aged lung Treg cells fail to upregulate a prorepair transcriptional prog...
(A) MA plot comparing gene expression of young Treg cells during the naive state with young Treg cells during the recovery phase of influenza infection. Genes of interest are annotated and y axis denotes fold-change dynamic range. (B) MA plot comparing gene expression of aged Treg cells during the naive state with aged Treg cells during the recovery phase of influenza infection. Genes of interest are annotated and y axis denotes fold-change dynamic range. Note that the y axis extends to +8 in A and +5 in B. (C and D) GSEA dot plot results highlighting key statistics (FDR q value and normalized enrichment score or NES) and enriched gene sets per phenotype. Genes were ordered by log2(fold change) and ranked by the young Treg cell–influenza (C) or aged Treg cell–influenza (D) phenotype. Red dots denote gene sets with a positive enrichment score or enrichment at the top of the ranked list. Blue dots denote gene sets with a negative enrichment score or enrichment at the bottom of the ranked list. (E and F) Top 3 GSEA positive enrichment plots for the young Treg cell–influenza (E) or aged Treg cell–influenza (F) phenotype. n = 5 mice/group (young — naive, aged — naive, young — influenza, and aged — influenza) for all panels.