DNA-dependent protein kinase catalytic subunit mediates T-cell loss in rheumatoid arthritis.
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.
Shao
Lan
L
Department of Medicine, Immunology and Rheumatology, Stanford University, Stanford, CA, USA.
Goronzy
Jörg J
JJ
Weyand
Cornelia M
CM
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000368:Aged; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D000072224:Bcl-2-Like Protein 11; D020134:Catalytic Domain; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007108:Immune Tolerance; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; C486655:BMF protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D051747:DNA-Activated Protein Kinase; D048670:MAP Kinase Kinase 4