Abstract
In the autoimmune syndrome rheumatoid arthritis (RA), T cells and T‐cell precursors have age‐inappropriate shortening of telomeres and accumulate deoxyribonucleic acid (DNA) double strand breaks. Whether damaged DNA elicits DNA repair activity and how this affects T‐cell function and survival is unknown. Here, we report that naïve and resting T cells from RA patients are susceptible to undergo apoptosis. In such T cells, unrepaired DNA stimulates a p53‐ataxia telangiectasia mutated‐independent pathway involving the non‐homologous‐end‐joining protein DNA‐protein kinase catalytic subunit (DNA‐PKcs). Upregulation of DNA‐PKcs transcription, protein expression and phosphorylation in RA T cells co‐occurs with diminished expression of the Ku70/80 heterodimer, limiting DNA repair capacity. Inhibition of DNA‐PKcs kinase activity or gene silencing of DNA‐PKcs protects RA T cells from apoptosis. DNA‐PKcs induces T‐cell death by activating the JNK pathway and upregulating the apoptogenic BH3‐only proteins Bim and Bmf. In essence, in RA, the DNA‐PKcs‐JNK‐Bim/Bmf axis transmits genotoxic stress into shortened survival of naïve resting T cells, imposing chronic proliferative turnover of the immune system and premature immunosenescence. Therapeutic blockade of the DNA‐PK‐dependent cell‐death machinery may rejuvenate the immune system in RA.