Table 1.
Main differences between cell senescence, quiescence, terminal differentiation, and T-cell exhaustion.
| Senescence | Quiescence | Terminal Differentiation | T-Cell Exhaustion | References | |
|---|---|---|---|---|---|
| Type of cell cycle arrest | Generally irreversible | Reversible | Generally irreversible | Largely irreversible | [26,27,29,30] |
| Cause | Repetitive stimulation; DNA damage agents; stress signals |
Signals of mitogen deprivation; contact inhibition |
Genetically preprogramed | Continuous antigenic stimulation |
[26,27,31,32] |
| Typical features | Large flat cells | Reduced cell size | n/a | n/a | [33,34] |
| Cell cycle arrest driver: ↑ p16, p21, p53 |
CDK inhibitors: ↑ p21,27, 57 |
p21, p27, and p57 | ↑ p27, p15; ↓ cyclin E-Cdk2, Cdc25A |
[26,27,31,35] | |
| ↑ Macromolecular damage ↓ Telomere length, telomerase activity |
Does not exhibit macromolecular damage | Does not exhibit macromolecular damage | ↓ Telomere length, telomerase activity | [36,37,38] | |
| ↑ SA-β-gal activity | Does not result in the upregulation of SA-β-gal activity | Does not result in the upregulation of SA-β-gal activity | Does not result in the upregulation of SA-β-gal activity |
[39,40] | |
| n/a | n/a | n/a | ↑ Inhibitory receptors: PD1, TIM3, LAG3, CTLA4, TIGIT |
[41] | |
| ↑ Glycolysis | ↓↑ Glycolysis (depending on cell type) |
n/a | ↓ Glycolysis | [42,43,44] | |
| Cytokine pattern | SASP, proinflammatory cytokines: ↑ IL-1, IL-6, IL-8, IFN-γ, TNF |
n/a | n/a | ↓ IL-2 ↓ TNF ↓ IFN-γ, β-chemokines |
[45,46] |
| Epigenetic changes | ↑ SAHF Abnormal DNA methylation |
↑ H3K27me3 chromatin modifications; expression level of several histones is strongly reduced |
↑ H3K9me3 and H3K27me3; reduced levels of global DNA methylation; enhancers are enriched for H3K27me3 and DNA methylation, which is associated with the lower expression of their target genes |
Exhaustion-associated DNA methylation patterns |
[37,47,48,49] |
CDC25A: M-phase inducer phosphatase 1; CDK: cyclin-dependent kinase; CTLA-4: cytotoxic T-lymphocyte antigen 4; H3K27me3: trimethylation of lysine 27 on histone H3 protein; H3K9me3: trimethylation of lysine 9 on histone H3 protein; IFN-γ: interferon gamma; IL: interleukin; LAG-3: lymphocyte-activation gene 3; p16: cyclin-dependent kinase inhibitor 2A; p21: cyclin-dependent kinase inhibitor 1; p27: cyclin-dependent kinase inhibitor 1B; p53: cellular tumor antigen p53; p57: cyclin-dependent kinase inhibitor 1C; PD-1: programed cell death protein 1; SA-β-gal: senescence-associated beta-galactosidase; SAHF: senescence-associated heterochromatic foci; SASP: senescence-associated secretory phenotype; TIGIT: T-cell immunoreceptor with Ig and ITIM domains; TIM3: T-cell immunoglobulin and mucin domain-containing protein 3; TNF-α: tumor necrosis factor alpha; ↑: increase; ↓: decrease.