Sensing of DNA double-strand breaks by the NHEJ system stabilizes RORγt transcriptional activity and shapes Th17 pathogenicity in autoimmunity.

Robust mitochondrial ROS production induces extensive double-strand breaks (DSBs) in telomeric DNA of effector T cells, where the DNA repair machinery is rapidly hyper-evoked to sense and ligate DSBs during the respiratory burst. However, whether effector T cells can exploit the DNA repair system to simultaneously potentiate their functional activation remains largely unknown, especially in the context of autoimmunity. Here, we demonstrate that non-homologous end joining (NHEJ), a predominant mechanism of DNA repair, is highly activated in pathogenic T helper 17 (pTh17) cells and exerts a previously unrecognized effect on shaping the pathogenic nature of pTh17s to trigger autoimmunity. Mechanistically, the perception of DSBs by KU proteins facilitates auto-phosphorylation of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), which stabilizes RORγt to bind to the promoters of effector-gene loci, thus initiating the pTh17 effector program to induce autoimmunity. Using mass spectrometry and transcriptome analyses, we identified IER2 as a novel NHEJ factor that potentiates DNA-PKcs kinase activity in response to IL-23R stimulation, which is necessary for shaping Th17 pathogenicity. Therefore, targeting the immuno-pattern of the NHEJ system shows potential for the treatment of autoimmune diseases.