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 4

Proliferating old CD4+ T cells have increased replication stress.

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Proliferating old CD4+ T cells have increased replication stress. (A–C) ...
(A–C) Naive CD4+ T cells from young and old individuals were activated for 5 days. Cycling cells were sorted based on DNA content. (A) Quantitative RT-PCR of indicated transcripts associated with ATR signaling. Results, normalized to ACTB, are presented for old relative to cycling young cells (n = 6, mean ± SEM). (B) Immunoblot for p-RPA32 (S8), p-CHK1 (S345), γH2aX (S139), and p21 and summary graphs of normalized intensities from 8 young (Y) and 7 old (O) individuals (mean ± SEM). (C) Immunoblot for p53 and summary graph (n = 7, mean ± SEM). (D) GSEA of p53 transcriptional targets in activated old naive CD4+ T cells relative to their expression in young cells (left) and heatmap of selected genes from RNA-seq data (right) (SRA: SRP158502). (E) Naive CD4+ T cells from young adults were activated and transduced with shCtrl or shNPAT lentivirus for 6 days. Expression of indicated p53 target genes was determined in transduced cells by quantitative RT-PCR. Results, normalized to ACTB, are presented relative to shCtrl+ cells (n = 5). Comparisons by 2-tailed, unpaired (A–C) or paired Student’s t test (E), with correction for multiple comparisons using Holm’s step-down adjustment in E. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. NS, not significant.