Figure 3.

Hallmarks of senescent CD4⁺CD28⁻ T lymphocytes. In contrast to their non-senescent counterpart, senescent CD4⁺CD28⁻ T lymphocytes show activation of the DNA damage response (DDR) by ataxia-telangiectasia mutated (ATM) and phosphorylation of H2A histone family member X (γ-H2AX). ATM signaling in these cells leads to phosphorylation of AMP-activated protein kinase (AMPK) and subsequently through a sestrin-mediated signaling pathway to p38 MAPK. Senescent CD4⁺CD28⁻ T lymphocytes also show increased secretion of pro-inflammatory and cytotoxic mediators attributed to a senescence-associated secretory phenotype (SASP) and upregulated cell cycle inhibitors, such as p16^ink4a, that block cell cycle progression from the G1 to the S phase. In addition, they have lysosomal dysfunction, as evidenced by increased senescence-associated-β-galactosidase (SA-βgal) activity, and are highly resistant to apoptosis by upregulating anti-apoptotic proteins such as Bcl-2 and cellular Flice-inhibitory protein (c-Flip).