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

Abstract

Mitochondrial dysfunction is a hallmark of IPF and promotes the development of pulmonary fibrosis. Mitochondrial stress can activate innate immunity via mitochondrial (mt) DNA sensing. However, whether mitochondrial stress also regulates adaptive immune is unknown. We here investigated regulation of MHC I antigen presentation by mitochondrial stress using a mouse cell model of chronic mitochondrial dysfunction as well as an acute mtDNA stress model in human primary lung fibroblasts(phLF). Mouse embryonic fibroblasts derived from the mitochondrial function, PolgA mutator mouse model, demonstrated concerted upregulation of the MHC I as revealed by proteomic and FACS analysis. Importantly, 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 signaling via the cGAS/STING. And CD8+ T cells were activated when co-cultured with the PolgA mutator cells. In phLF, transfected mtDNA increased the immunoproteasome/MHC I and promoted generation of influenza MHC class I antigenic peptides to activate influenza-specific CD8+T cells as shown by FACS analysis and CD8+ T cell activation assays. Furthermore, single cell RNA seq analysis from publicly available ILD data sets revealed an enrichment for type I interferon and MHC I in AT1 and ciliated cells as well as CD8+ T cell responses. In conclusion, dysfunctional mitochondria activate adaptive CD8+ T cell responses via immunoproteasome and MHC I antigen presentation. In the lung, the defective mitochondrial function might contribute to fibrosis via imbalanced MHC class I antigen presentation in lung epithelial cells driving T cell autoimmunity.