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.
View: Text | PDF
Research Article Aging Article has an altmetric score of 11

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

×

Figure 6

SIRT1 inhibition in replicating old human T cells restores cell cycle progression and diminishes the replication-stress response.

Options: View larger image (or click on image) Download as PowerPoint
SIRT1 inhibition in replicating old human T cells restores cell cycle pr...
(A and B) Naive CD4+ T cells from old individuals were activated for 5 days. DMSO or Ex-527 was added on day 2. (A) Day 5 activated cells were pulsed with EdU for 2 hours, followed by BrdU for 1 hour. Representative flow plots of BrdU and EdU incorporation (left) and summary graphs of BrdU–EdU+ cell frequencies and percentages of BrdU–EdU+ S-exit cells among EdU+ cells (right; n = 7, mean). (B) Immunoblots of indicated proteins in cycling cells from 6 old adults (mean ± SEM). (C) 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 = 3). (D) Immunoblots for p53 in cycling cells in experiments with 3 old adults. (E) Expression of indicated p53 transcriptional target genes in cycling old cells was determined by quantitative RT-PCR. Results are presented relative to DMSO-treated cells (n = 5). (F) Number of activated naive CD4+ T cells from 9 old adults recovered on day 5 (mean). Comparisons by 2-tailed, paired Student’s t test (A, B, E, and F), with correction for multiple comparisons using Holm’s step-down adjustment in E. *P < 0.05, **P < 0.01, ***P < 0.001.