Abstract
Patients in RA have premature aging of the immune system, with accumulation of pro-inflammatory and tissue-destructive T cells. Accelerated immune senescence has been attributed to chronic T cell loss. Naïve T cells in RA have a defect in repairing damaged DNA. We have examined whether chronic stimulation of DNA repair mechanisms affects T cell survival in RA. Naïve CD4+CD45RA+ T cells from RA patients had a higher load of double-stranded DNA breaks (p=0.0005) and spontaneous apoptosis rates (p=0.03) than in healthy controls. High DNA damage failed to upregulate the ATM-p53 axis. Instead, the transcript and protein levels of the DNA repair enzyme DNA-PKcs were elevated. Induction of DNA-PKcs was disease-specific and not found in patients with SLE. Knocking down DNA-PKcs transcription or inhibiting enzyme activity with a kinase inhibitor normalized T cell apoptosis rates in patients. Activation of DNA-PKcs was correlated with stimulation of SAPK/JNK pathway. Inhibition of either DNA-PKcs or JNK suppressed the pro-apoptotic protein Bim and protected T cells from apoptotic death. T cells in RA patients accumulate damaged DNA, causing chronic induction of repair activity. DNA double-strand breaks are recognized by a ATM-independent pathway involving DNA-PKcs. Due to the activation of the JNK-Bim death signaling cascade, RA T cells are apoptosis sensitive. Therapeutic blockade of DNA-PK-dependent cell death machinery could help rejuvenate the immune system of RA patients.
