T Cells Produce Type I Interferon in the Trex1 D18n Model of Cgas-sting-dependent Interferonopathy
Year: 2020
Type: dissertation
Abstract: Autoimmunity can result when cells fail to properly dispose of DNA. Mutations in the DNA-degrading Three-prime Repair EXonuclease 1 (TREX1) cause a spectrum of human autoimmune diseases resembling Systemic Lupus Erythematosus (SLE). The pathogenic mechanism is thought to involve sensing of undegraded TREX1 DNA substrates by cyclic GMP-AMP synthase (cGAS)-STimulator of INterferon Genes (STING), leading to chronic production of the inflammatory cytokine type I interferon (IFN-I) and loss of self-tolerance. However, previous studies have utilized a model system in which other sources of inflammatory signaling could contribute to pathogenesis. In this study, we utilize a unique mouse model of TREX1 catalytic inactivity to demonstrate that IFN-I and STING are required for pathogenesis, confirming the link between failed DNA degradation, DNA sensing, and immune activation. We further demonstrate that bone marrow-derived cells drive the development of autoimmunity in TREX1-deficient mice. We identify both innate immune and surprisingly, activated T cells as sources of pathological IFN-α production. These findings demonstrate that TREX1 enzymatic activity is crucial to prevent inappropriate DNA-sensing and IFN-I production in immune cells, including normally low-level IFN-α-producing cells. These results expand our understanding of DNA sensing and innate immunity in T cells, and may have relevance to the pathogenesis of human disease caused by TREX1 mutation.
Author: Simpson, Sean
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7043756203