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 8

SIRT1 inhibition augments antigen-specific T cell responses in vivo.

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SIRT1 inhibition augments antigen-specific T cell responses in vivo. (A–...
(A–C) WT or miR-181a–/– SMARTA cells were transferred into B6 hosts before infection with LCMV. DMSO or Ex-527 was given i.p. daily starting the day after the infection. On day 5 after infection, mice were injected with BrdU 1 hour prior to harvest. (A) Representative flow plots of BrdU incorporation and DNA content and summary data (mean ± SEM). (B) Immunoblots of SMARTA cells. (C) Number of SMARTA cells in the spleen (mean ± SEM). (D and E) WT and miR-181a–/– mice were infected with LCMV and given DMSO or Ex-527 daily. (D) Number of Db LCMV GP33-tetramer+ CD8+ T cells on day 7 (mean ± SEM). (E) Viral titers on day 6 after LCMV infection (mean ± SEM). (F–I) miR-181a–deficient SMARTA T cells were retrovirally transduced with either shCtrl or shSirt1. (F) Immunoblots of shRNA+ cells and summary graphs (n = 4, mean). (G) Sorted shCtrl+ or shSirt1+ miR-181a–deficient SMARTA cells were transferred into B6 hosts, followed by LCMV infection. On day 5, mice were injected with BrdU 1 hour prior to harvest. Representative flow plots of BrdU incorporation and DNA content and summary data (mean ± SEM). (H) Immunoblots of shRNA+ cells. (I) Number of shRNA+ SMARTA cells in the spleen (mean ± SEM). Data are pooled from 3 independent experiments with 6–10 mice per group (A and C), representative of 3 independent experiments with 2 mice per group (B), pooled from 2 experiments with 5–10 mice per group (D and E), or 1 experiment with 4–5 mice per group (F–I). Comparisons by 1-way ANOVA followed by Tukey’s post hoc test (A and C–E) and paired (F) or unpaired Student’s t test (G and I). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. NS, not significant.