Defective induction of the proteasome associated with T-cell receptor signaling underlies T-cell senescence

Genes Cells. 2019 Dec;24(12):801-813. doi: 10.1111/gtc.12728. Epub 2019 Nov 6.


The proteasome degradation machinery is essential for a variety of cellular processes including senescence and T-cell immunity. Decreased proteasome activity is associated with the aging process; however, the regulation of the proteasome in CD4+ T cells in relation to aging is unclear. Here, we show that defects in the induction of the proteasome in CD4+ T cells upon T-cell receptor (TCR) stimulation underlie T-cell senescence. Proteasome dysfunction promotes senescence-associated phenotypes, including defective proliferation, cytokine production and increased levels of PD-1+ CD44High CD4+ T cells. Proteasome induction by TCR signaling via MEK-, IKK- and calcineurin-dependent pathways is attenuated with age and decreased in PD-1+ CD44High CD4+ T cells, the proportion of which increases with age. Our results indicate that defective induction of the proteasome is a hallmark of CD4+ T-cell senescence.

Keywords: T cell receptor signal; T cell senescence; aging; proteasome.

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / metabolism*
  • CD4-Positive T-Lymphocytes / physiology
  • Cell Proliferation
  • Cells, Cultured
  • Cellular Senescence*
  • Cytokines / genetics
  • Cytokines / metabolism
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Phenotype
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / metabolism
  • Proteasome Endopeptidase Complex / metabolism*
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism*
  • Signal Transduction


  • Cytokines
  • Hyaluronan Receptors
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptors, Antigen, T-Cell
  • Proteasome Endopeptidase Complex