Histone deficiency and accelerated replication stress in T cell aging
Chulwoo Kim, … , Cornelia M. Weyand, Jörg J. Goronzy
Chulwoo Kim, … , Cornelia M. Weyand, Jörg J. Goronzy
Published June 1, 2021
Citation Information: J Clin Invest. 2021;131(11):e143632. https://doi.org/10.1172/JCI143632.
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Research Article Aging

Histone deficiency and accelerated replication stress in T cell aging

Abstract

With increasing age, individuals are more vulnerable to viral infections such as with influenza or the SARS-CoV-2 virus. One age-associated defect in human T cells is the reduced expression of miR-181a. miR-181ab1 deficiency in peripheral murine T cells causes delayed viral clearance after infection, resembling human immune aging. Here we show that naive T cells from older individuals as well as miR-181ab1–deficient murine T cells develop excessive replication stress after activation, due to reduced histone expression and delayed S-phase cell cycle progression. Reduced histone expression was caused by the miR-181a target SIRT1 that directly repressed transcription of histone genes by binding to their promoters and reducing histone acetylation. Inhibition of SIRT1 activity or SIRT1 silencing increased histone expression, restored cell cycle progression, diminished the replication-stress response, and reduced the production of inflammatory mediators in replicating T cells from old individuals. Correspondingly, treatment with SIRT1 inhibitors improved viral clearance in mice with miR-181a–deficient T cells after LCMV infection. In conclusion, SIRT1 inhibition may be beneficial to treat systemic viral infection in older individuals by targeting antigen-specific T cells that develop replication stress due to miR-181a deficiency.

Authors

Chulwoo Kim, Jun Jin, Zhongde Ye, Rohit R. Jadhav, Claire E. Gustafson, Bin Hu, Wenqiang Cao, Lu Tian, Cornelia M. Weyand, Jörg J. Goronzy

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Figure 7

Replication stress accounts for the activation of proinflammatory pathways in CD4+ T cell responses in old adults.

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Replication stress accounts for the activation of proinflammatory pathwa...
(A) GSEA of gene signatures of cellular senescence and SASP in activated old (O) naive CD4+ T cells relative to their expression in young (Y) cells (left) and heatmaps of selected genes from RNA-seq data (right; SRA: SRP158502). (B and C) Expression of indicated genes associated with inflammatory mediators was determined by quantitative RT-PCR in shCtrl+ or shNPAT+ cells (B) and in DMSO- or Ex-527–treated cells (C). Results, normalized to ACTB, are presented relative to shCtrl+ or DMSO-treated cells, respectively (n = 5). (D) Immunoblots for p16 in activated, proliferating naive CD4+ T cells from 3 young and 3 old adults. CD45RA+CCR7– terminally differentiated effector memory cells (CD8+ Temra) are included as positive control for p16 expression. (E) Naive CD4+ T cells from young and old individuals were activated for 8 days. Histograms of green fluorescence, indicative of senescence-associated β-galactosidase activity (left), and summary graph of geometric MFI (right) from 7 young and 7 old individuals (mean ± SEM). The filled gray histogram represents no substrate. (F) Histograms of senescence-associated β-galactosidase activity on shCtrl+ or shNPAT+ cells from 1 young adult. (G) Histograms of senescence-associated β-galactosidase activity in DMSO- or Ex-527–treated cells and summary graph from 3 old adults (mean). Comparisons by 2-tailed, paired (B, C, and G) or unpaired Student’s t test (E), with correction for multiple comparisons using Holm’s step-down adjustment in B and C. *P < 0.05, **P < 0.01, ***P < 0.001. NS, not significant.