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 5

miR-181a–dependent increase in SIRT1 expression represses histone gene transcription.

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miR-181a–dependent increase in SIRT1 expression represses histone gene t...
(A) Equal numbers of congenically marked WT and miR-181a–/– YFP+ SMARTA cells were cotransferred into B6 mice before infection with LCMV. Immunoblots for SIRT1 and histone H3-K9/14 acetylation (H3K9/14Ac) of splenic SMARTA cells on day 7, representative of 3 experiments with 2 to 3 mice per group. (B–D) Human young (Y) and old (O) naive CD4+ T cells were activated for 5 days. Immunoblots for SIRT1 and histone H3K9/14Ac (B) and NPAT (C) in cycling cells (left); summary graphs of normalized intensities from 4–6 young and 4–6 old individuals (right, mean ± SEM). (D) CUT&RUN assay of SIRT1 binding and histone H3K9/14Ac enrichment at indicated histone gene promoters from 5 experiments with 1 young and 1 old individual each. Results are presented relative to cycling young cells (mean ± SEM). (E–G) Naive CD4+ T cells from old individuals were activated for 5 days. DMSO or Ex-527 was added on day 2. (E) Immunoblots of SIRT1 and histone H3K9/14Ac in cycling cells and summary data from 5 old adults (mean ± SEM). (F) Expression of indicated histone genes in cycling cells was determined by quantitative RT-PCR. Results are presented relative to DMSO-treated cells (n = 6, mean ± SEM). Differences in expression of all histone genes are statistically significant (P < 0.01), except for HIST1H4B (P = 0.25), after correction for multiple comparisons using Holm’s step-down adjustment. (G) Immunoblots of histones in cycling cells and summary data from 7 old adults (mean ± SEM). (H) Naive CD4+ T cells from old adults were activated with anti-CD3/anti-CD28 beads and transduced with control (shCtrl) or SIRT1 (shSIRT1) shRNA lentivirus for 6 days. Immunoblots for indicated proteins in shRNA+ cells (n = 2). Comparisons by 2-tailed, unpaired (B and C) or paired Student’s t test (D–G). *P < 0.05, **P < 0.01. NS, not significant.