Leite, J. A.; Notaberardino Bos, N.; Menezes, L.; Martins, E.; da Silva Leandro, G.; da Silva, P.; Ranfley, H.; Oliveira, S.; Pontes Ferreira, C.; Arimateia de Oliveira Nery Neto, J.; Yuji, V.; Cipelli, M.; Leocata, B.; Goncalves, T.; Gabry da Silveira, A.; Baroni, S.; L. Weiner, H.; Hofmann, T.; Scheu, S.; Machado Colli, L.; Waisman, A.; Muxel, S.; Menck, C. F.; Saraiva Camara, N. O.

Th17 cells are critical for mucosal immunity, producing IL-17A, IL-17F, and IL-22, but dysregulated Th17 responses are implicated in autoimmune diseases. Despite their susceptibility to oxidative stress in certain conditions, Th17 cells exhibit reduced oxidative DNA damage and cell death compared to other T helper subsets. However, the mechanisms that protect Th17 cells from oxidative stress are poorly understood. Here, we identify Xeroderma Pigmentosum Complementation Group C (XPC) as a key regulator of DNA repair and genomic stability in Th17 cells. In XPC-deficient mice, we demonstrate that the absence of XPC impairs Th17 differentiation, as evidenced by reduced expression of key differentiation markers, including Rorc and Il17a, along with decreased IL-17A production. This deficiency leads to increased oxidative stress, DNA damage, and a metabolic shift from glycolysis to oxidative phosphorylation. Moreover, the transcription factor BATF directly regulates XPC expression, linking the BATF-XPC axis to the maintenance of Th17 cell function. Importantly, we find that restoring antioxidant capacity with N-Acetylcysteine (NAC) rescues IL-17A production and reduces DNA damage in XPC-deficient Th17 cells. Mechanistically, we find that XPC interacts with OGG1, a DNA glycosylase involved in the repair of oxidative DNA damage, highlighting XPC\'s role in maintaining genomic integrity during Th17 cell differentiation. Our findings reveal a previously unrecognized role for XPC in protecting Th17 cells from oxidative stress, ensuring their proper differentiation and function, with potential implications for targeting DNA repair pathways in autoimmune and inflammatory diseases.