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284 T cells produce interferon alpha in a model of lupus-like disease
  1. Sean Simpson1,
  2. Stephen Rego2,
  3. Scott Harvey2,
  4. Jason Grayson2 and
  5. Fred Perrino2
  1. 1Wake Forest School of Medicine
  2. 2Wake Forest University School of Medicine


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.

Abstract 284 Figure 1

TREX1 D18N T cells spontaneously generate IFN-a. (A) Kaplan-Meir survival curve demonstrating the absence of autoimmune mortality in TREX1 D18N IFNAR KO animals. (B) qRT-PCR measurement of IFN- gene expression in uninfected WT splenocytes, LCMV +splenocytes, purified LCMV +non innate immune cells, and purified LCMV +innate immune cells (data represents cells from three virally-challenged mice 48 hours after infection). (C) IFN- gene expression in splenocytes from unchallenged WT and D18N mice (26–30 mice per genotype) (D) IFN- gene expression in whole splenocytes and purified non-innate and innate immune cells from both WT and D18N mice (3 separations, 6–8 mice per genotype) (E) qRT-PCR measurement of IFN- expression or ISG expression (F) in whole splenocytes or purified T and B cells from WT and D18N mice (3 separations, 3 mice of each genotype). (G) IFN- expression in sorted naïve or differentiated CD44high CD4 or CD8 T cells from both WT and D18N mice (3 independent sorts, 3 animals of each genotype). All mice were mixed sex and 8–12 weeks of age. Error bars represent SEM. *p<0.05, **p<0.01, ***p<0.001 ****p<0.0001 by Log-rank test (A), unpaired student’s t-test (C, WT vs. D18N comparisons in D-G), or one-way ANOVA (B, D18N splenocytes vs. other D18N populations in D-G).

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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