Background Failure to properly dispose of self-DNA can inappropriately trigger anti-viral defense systems, leading to autoimmunity. Indeed, mutations in the DNA exonuclease TREX1 are causative for a spectrum of rare lupus-like autoimmune diseases in humans. These disorders involve triggering of the cytosolic dsDNA sensor cyclic GMP-AMP Synthase (cGAS) and the STimulator of INterferon Genes (STING), leading to chronic production of the anti-viral cytokine type I interferon (IFN-I) and the development of autoimmunity. Importantly, the exact cells in which the sensing of undegraded DNA and subsequent production of IFN-I occur remain unknown.
Methods We generated a mouse expressing the catalytically inactive TREX1 D18N allele, which causes familial chilblain lupus in humans. We examined anti-viral gene expression and the phenotype of these mice to study the immunological effects of losing TREX1 activity. We performed bone marrow transplants to determine if autoimmune pathogenesis in this model was dependent on hematopoietic or non-hematopoietic cells. Finally, we measured expression of type I interferon is various purified cell populations to identify specific cellular producers contributing to autoimmune pathogenesis.
Results In this study, we demonstrate that TREX1 catalytic inactivity induces IFN-I signaling and lupus-like autoimmunity in a mouse. Moreover, we show that TREX1 deficiency within bone marrow-derived cells causes IFN-I activation and the development of autoimmunity. We provide evidence of spontaneous IFN- production within both innate immune and T cells. T cell IFN-a expression was observed in all T cell populations, but was most enriched within naive T cells. We also demonstrate that D18N T cells express all components of the cGAS-STING pathways and generate IFN-I protein, both spontaneously and in response to small-molecule activation of STING.
Conclusions Our findings demonstrate that TREX1 enzymatic activity is crucial to prevent inappropriate DNA-sensing and IFN-I production. TREX1 inactivity within hematopoietic cells was both necessary and sufficient to induce lupus-like autoimmunity, indicating that TREX1 normally acts within immune cells to suppress inappropriate activation of anti-viral signaling. Both innate immune and T cells respond to TREX1 dysfunction by spontaneously synthesizing IFN-, a surprising result given that T cells are not canonically thought to be major IFN--producing cells. These results expand our understanding of the pathogenesis of lupus-like disease, and indicate that small molecule inhibition of TREX1 could represent an appealing strategy for anti-viral and cancer immune-therapies.
Funding Source(s): NIH grant -- 5R01AI116725–03
NIH training grant -- 5T32AI007401–23
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