Mitochondrial DNA stress in lung parenchymal cells activates autoreactive CD8 T cells - implications for pulmonary fibrosis

Abstract

Mitochondrial dysfunction, mtDNA release and activation of cGAS/STING signaling are known pathomechanistic features of pulmonary fibrosis and have been related to the activation of innate immune responses. We here investigated whether mitochondrial stress also activates adaptive immunity.

In this study, we demonstrate that mtDNA stress in lung parenchymal cells activates autoreactive CD8⁺ T cells by upregulating the immunoproteasome and MHC class I antigen presentation pathway via cGAS/STING/type I interferon signaling. This type I interferon-induced adaptive immune activation is a conserved phenomenon in mice and men occurring in both lung epithelium and mesenchyme. In patients with idiopathic pulmonary fibrosis, chronic activation of the type I interferon/immunoproteasome/MHC class I pathway in lung epithelial cells concurs with CD8⁺ T cell activation in fibrotic lung tissue. Moreover, using the Munich IPF cohort, we corroborate that the number of effector CD8⁺ T cells is also elevated systemically in IPF patients.

Our results thus support a novel concept where intracellular mtDNA stress in epithelial or mesenchymal cells triggers autoreactive CD8⁺ T cell activation thereby contributing to autoimmune-mediated tissue damage and subsequent irreversible fibrotic scarring of the lung. We believe that our findings are not restricted to lung fibrosis but may represent a conserved pathomechanism for development of organ fibrosis induced by mitochondrial or genomic DNA stress (e.g. upon telomere dysfunction) or aberrant type I interferon signaling e.g. upon chronic virus infections or in long-COVID-19 patients.