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

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 CD44 CD4 T cells. Proteasome induction by TCR signaling via MEK-, IKK- and calcineurin-dependent pathways is attenuated with age and decreased in PD-1 CD44 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.