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 3

Reduced histone expression promotes replication stress.

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Reduced histone expression promotes replication stress. Naive CD4+ T cel...
Naive CD4+ T cells from young adults were activated with anti-CD3/anti-CD28 beads and transduced with control (shCtrl) or NPAT (shNPAT) shRNA lentivirus for 6 days. (A) Immunoblots for NPAT in lentivirally transduced GFP+ cells and summary data of normalized intensities from 4 young adults (mean ± SEM). (B) Expression of indicated histone genes in sorted shRNA+ cells. Results, normalized to ACTB, are presented relative to shCtrl+ cells from 6 young adults (mean ± SEM). Differences in expression of all histone genes are statistically significant (P < 0.01), except for HIST1H1B (P = 0.03), HIST1H3B (P = 0.06), and HIST1H3D (P = 0.03), after correction for multiple comparisons using Holm’s step-down adjustment. (C) Immunoblots for histone H3 and H4 from shRNA+ cells and summary data of normalized intensities from 6 young adults (mean ± SEM). (D) Activated cells were pulsed with BrdU for 1 hour. Representative flow plots of BrdU incorporation and DNA content and summary data of frequencies (n = 5, mean). (E) Activated cells were pulsed with EdU for 2 hours, followed by BrdU for 1 hour. Percentage of BrdU–EdU+ S-exit cells among EdU+ cells from 3 young adults (mean). (F) Immunoblotting for p-RPA32 (S8), p-CHK1 (S345), γH2aX (S139), and p21 on sorted shRNA+ cells (left) and summary graphs of mean normalized intensities from 6 young adults (right, mean ± SEM). Comparisons by 2-tailed, paired Student’s t test (A–F). *P < 0.05, **P < 0.01.