Age-independent and targetable transcription factor networks regulate CD8+ T cell senescence in aging humans

Aging impairs immunity in part through the accumulation of CD8+ T cells with senescence features, including a pro-inflammatory transcriptome and impaired proliferative capacity. Using senescent cell isolation coupled with multiomic profiling, we defined the epigenetic regulation of CD8+ T cell senescence in healthy younger and older humans. We discovered that the transition to senescence was controlled by chromatin state-specific transcription factor (TF) networks whose composition was largely insensitive to donor age. These TF networks mediated widespread enhancer remodeling, causing repression of genes essential for proliferation as well as upregulation of inflammatory and secretory pathways. Inhibition of AP1, KLF5, or RUNX2 modulated the transcriptional output and partially restored the blunted transcriptional response to stimulation of senescent CD8+ T cells. Our data also revealed CD8+ T cell senescence gene signatures predictive of response to CAR-T cell therapy in diffuse large B cell lymphomas. Overall, our study defines the gene regulatory mechanisms of senescence in human CD8+ T cells, provides a resource for the interrogation of CD8+ T cell senescence in disease, highlights TF network perturbation as a viable strategy to manipulate the senescence state of CD8+ T cells, and reveals senescent CD8+ T cell gene signatures as valuable prognostic tools for immunotherapy outcome.