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T CELLS PRODUCE TYPE I INTERFERON IN THE TREX1 D18N MODEL OF CGAS-STING-DEPENDENT INTERFERONOPATHY

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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.
subject
Autoimmunity
cGAS-STING
Innate immunity
Interferonopathy
T cells
TREX1
contributor
Simpson, Sean (author)
Perrino, Fred (committee chair)
Alexander-Miller, Martha (committee member)
Hollis, Thomas (committee member)
Lyles, Doug (committee member)
date
2020-08-28T08:35:21Z (accessioned)
2020-08-28T08:35:21Z (available)
2020 (issued)
degree
Biochemistry and Molecular Biology (discipline)
identifier
http://hdl.handle.net/10339/96938 (uri)
language
en (iso)
publisher
Wake Forest University
title
T CELLS PRODUCE TYPE I INTERFERON IN THE TREX1 D18N MODEL OF CGAS-STING-DEPENDENT INTERFERONOPATHY
type
Dissertation

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