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.
| Original language | English |
|---|---|
| Article number | e143632 |
| Journal | Journal of Clinical Investigation |
| Volume | 131 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - 2021 Jun |
Bibliographical note
Funding Information:We thank C.Z. Chen (Stanford University) for providing miR-181ab1fl/fl mice; R. Ahmed (Emory University) for providing SMARTA mice, LCMV-Armstrong, BHK cells, and Vero cells; the NIH Tetramer Core Facility (Atlanta, Georgia, USA) for providing tetramers; Y.S. Choi (Seoul National University) for the LMPd-Am-etrine vector; and B. Carter of the Palo Alto Veterans Administration Flow Cytometry Core for assistance with flow cytometry and cell sorting. This work was supported by NIH grants R01 AR042527, R01 HL117913, R01 AI108906, R01 HL142068, and P01 HL129941 (to CMW); R01 AI108891, R01 AG045779, U19 AI057266, R01 AI129191 (to JJG); and with resources and the use of facilities at the Palo Alto Veterans Administration Healthcare System. Tetramers were provided by the NIH Tetramer Core Facility supported by contract HHSN272201300006C from the NIAID. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Funding Information:
We thank C.Z. Chen (Stanford University) for providing miR-181ab1fl/fl mice; R. Ahmed (Emory University) for providing SMARTA mice, LCMV-Armstrong, BHK cells, and Vero cells; the NIH Tetramer Core Facility (Atlanta, Georgia, USA) for providing tetramers; Y.S. Choi (Seoul National University) for the LMPd-Ametrine vector; and B. Carter of the Palo Alto Veterans Administration Flow Cytometry Core for assistance with flow cytometry and cell sorting. This work was supported by NIH grants R01 AR042527, R01 HL117913, R01 AI108906, R01 HL142068, and P01 HL129941 (to CMW); R01 AI108891, R01 AG045779, U19 AI057266, R01 AI129191 (to JJG); and with resources and the use of facilities at the Palo Alto Veterans Administration Healthcare System. Tetramers were provided by the NIH Tetramer Core Facility supported by contract HHSN272201300006C from the NIAID. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Publisher Copyright:
© 2021, American Society for Clinical Investigation.
ASJC Scopus subject areas
- Medicine(all)