Epigenetic mechanisms regulating CD8+ T cell senescence in aging humans

Area of Science:

• Immunology
• Cellular senescence
• Epigenetics

Background:

• Aging impairs immune function, increasing infection susceptibility in the elderly.
• CD8+ T cells accumulate senescent cells with age, characterized by inflammation and reduced proliferation.
• Senescent CD8+ T cells are linked to age-related diseases and treatment resistance.

Purpose of the Study:

• To investigate the epigenetic mechanisms regulating CD8+ T cell senescence.
• To identify key regulators of CD8+ T cell senescence.
• To explore therapeutic strategies targeting CD8+ T cell senescence.

Main Methods:

• Isolation of senescent CD8+ T cells.
• Multiomic profiling (transcriptomics, epigenomics).
• Pharmacological inhibition of transcription factor networks.

Main Results:

• Senescence-associated ß-galactosidase (SA-ßGal) activity drives global transcriptomic and chromatin accessibility changes.
• Enhancer remodeling represses functional genes and upregulates inflammatory/secretory genes.
• Transcription factor networks, largely age-insensitive, control senescence.
• Targeting TF networks modulated senescence.
• Senescence signatures predicted CAR T-cell therapy refractoriness and were enriched in systemic lupus erythematosus.

Conclusions:

• Multiomic profiling identifies key regulators of CD8+ T cell senescence.
• Senescent CD8+ T cells play a critical role in disease progression.
• Targeting TF networks offers a potential therapeutic approach for CD8+ T cell senescence.