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T Cells Produce IFN-α in the TREX1 D18N Model of Lupus-like Autoimmunity.


ABSTRACT: Autoimmunity can result when cells fail to properly dispose of DNA. Mutations in the three-prime repair exonuclease 1 (TREX1) cause a spectrum of human autoimmune diseases resembling systemic lupus erythematosus. The cytosolic dsDNA sensor, cyclic GMP-AMP synthase (cGAS), and the stimulator of IFN genes (STING) are required for pathogenesis, but specific cells in which DNA sensing and subsequent type I IFN (IFN-I) production occur remain elusive. In this study, we demonstrate that TREX1 D18N catalytic deficiency causes dysregulated IFN-I signaling and autoimmunity in mice. Moreover, we show that bone marrow-derived cells drive this process. 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.

SUBMITTER: Simpson SR 

PROVIDER: S-EPMC6946867 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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T Cells Produce IFN-α in the TREX1 D18N Model of Lupus-like Autoimmunity.

Simpson Sean R SR   Rego Stephen L SL   Harvey Scott E SE   Liu Mingyong M   Hemphill Wayne O WO   Venkatadri Rajkumar R   Sharma Rahul R   Grayson Jason M JM   Perrino Fred W FW  

Journal of immunology (Baltimore, Md. : 1950) 20191211 2


Autoimmunity can result when cells fail to properly dispose of DNA. Mutations in the three-prime repair exonuclease 1 (TREX1) cause a spectrum of human autoimmune diseases resembling systemic lupus erythematosus. The cytosolic dsDNA sensor, cyclic GMP-AMP synthase (cGAS), and the stimulator of IFN genes (STING) are required for pathogenesis, but specific cells in which DNA sensing and subsequent type I IFN (IFN-I) production occur remain elusive. In this study, we demonstrate that TREX1 D18N cat  ...[more]

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