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 1

miR-181a deficiency impairs histone expression and cell cycle progression in murine antiviral responses.

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miR-181a deficiency impairs histone expression and cell cycle progressio...
(A–E) Equal numbers of congenically marked WT and miR-181a–/– YFP+ SMARTA cells were cotransferred into B6 mice before LCMV infection. (A) Experimental scheme (left), representative flow plots of WT and miR-181a–/– SMARTA cells (middle), and SMARTA frequencies (right, mean ± SEM). (B and C) RNA-seq of WT and miR-181a–/– SMARTA CD4+ T cells on day 7 after LCMV infection. (B) GSEA of cell cycle gene signature in WT relative to miR-181a–/– SMARTA cells. (C) Volcano plot of core histone genes (red indicates adjusted P < 0.05). (D) Immunoblotting for histones in WT and miR-181a–/– SMARTA cells on day 7 after LCMV infection. (E) On day 5 after LCMV infection, recipient mice received BrdU for 1 hour prior to spleen harvest. Representative flow plots of BrdU incorporation and DNA content and summarized frequencies (mean ± SEM). (F and G) WT and miR-181a–/– mice infected with LCMV were injected with BrdU. (F) Number of Db LCMV GP33-tetramer+ CD8+ T cells (mean ± SEM). (G) Representative flow plots of BrdU incorporation and DNA content in tetramer+ CD8+ T cells (left) and summary of frequencies (right, mean ± SEM). (H) GSEA of the p53-induced gene set in WT relative to miR-181a–/– SMARTA cells. (I) Immunoblots for p53 on day 7 SMARTA cells and summary data of mean normalized intensities. (J) Immunoblots of SMARTA cells on day 7 after LCMV infection. Data are representative of 3 experiments with 3 to 5 mice per group (A and D), 1 experiment with 4 mice per group (B, C, and H), or representative of 2 experiments with 2 to 6 mice per group (E–G, I, and J). Comparison by 2-tailed, paired (A, E, and I) or unpaired Student’s t test (F and G). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. NS, not significant.