Histone deficiency and accelerated replication stress in T cell aging.

Area of Science:

• Immunology
• Molecular Biology
• Aging Research

Background:

• Older individuals exhibit increased susceptibility to viral infections.
• Age-associated decline in T cell function, specifically reduced miR-181a expression, contributes to impaired immunity.
• miR-181a deficiency in T cells mimics aspects of immune aging and leads to delayed viral clearance.

Purpose of the Study:

• To investigate the molecular mechanisms underlying age-related T cell dysfunction.
• To explore the role of miR-181a and its target SIRT1 in T cell replication stress.
• To evaluate the therapeutic potential of SIRT1 inhibition for enhancing antiviral immunity in aging.

Main Methods:

• Analysis of T cells from elderly individuals and miR-181a-deficient mice.
• Assessment of histone expression, cell cycle progression, and replication stress in activated T cells.
• Investigated the regulatory role of SIRT1 on histone gene transcription and acetylation.
• Utilized SIRT1 inhibition and silencing in vitro and in vivo models.
• Evaluated viral clearance in mice treated with SIRT1 inhibitors post-infection.

Main Results:

• Naive T cells from older individuals and miR-181a-deficient mice exhibit excessive replication stress post-activation.
• Reduced histone expression and delayed S-phase progression were observed, linked to SIRT1-mediated repression of histone genes.
• SIRT1 inhibition or silencing restored histone expression, normalized cell cycle, and reduced replication stress and inflammation.
• SIRT1 inhibitor treatment improved viral clearance in mice with miR-181a-deficient T cells after LCMV infection.

Conclusions:

• miR-181a deficiency in T cells causes age-related replication stress via SIRT1-mediated histone repression.
• SIRT1 inhibition emerges as a promising therapeutic strategy to bolster antiviral T cell responses in the elderly.
• Targeting SIRT1 in antigen-specific T cells may combat systemic viral infections in aging populations.