Mitochondrial DNA stress activates MHC class I antigen presentation and CD8+ T-cell immunity: implications for pulmonary fibrosis

Mitochondrial dysfunction is a hallmark of IPF and promotes the development of fibrosis. Mitochondrial stress has been shown to activate innate immunity via mitochondrial (mt) DNA sensing. However, whether mitochondrial stress regulates adaptive immune responses is unknown. We here investigated the regulation of MHC I antigen presentation by mitochondrial stress using a chronic mitochondrial dysfunction and an acute mtDNA stress model. Mouse embryonic fibroblasts derived from the PolgA mutator mouse, which represents a system of disturbed mitochondrial function, demonstrated concerted upregulation of the MHC I antigen presentation pathway as revealed by proteomic and FACS analysis. Importantly, the expression and activity of the immunoproteasome, a specialized type of proteasome involved in the generation of antigenic MHC I peptides, was strongly upregulated compared to controls. Induction was driven by the activation of STAT1/type I interferon via the cGAS/STING as shown by siRNA silencing. Upregulation of MHC I specifically activated CD8⁺ T cells by PolgA mutator cells. In primary mouse ATII cells and human lung fibroblasts, mtDNA increased the immunoproteasome/MHC I and promoted the generation of influenza MHC I antigenic peptides to activate influenza-specific CD8⁺T cells as shown by FACS and CD8⁺ T cell activation assay. MHC I and STING were elevated in AT1 and ciliated cells in IPF scRNAseq suggesting a disease-related STING/MHC I in pulmonary fibrosis. We are currently testing defective mitochondrial function that might contribute to fibrosis via imbalanced MHC class I antigen presentation in lung epithelial cells and driving T cell autoimmunity.