Type I Interferons induce TREX1 in myeloid dendritic cells. (108.10)

Abstract

Abstract Dendritic cells (DCs) are activated by endogenous and exogenous danger signals to stimulate T and B cell responses. Type I Interferons (IFNα/β) are endogenous danger signals able to activate DCs and induce the expression of IFN-stimulated genes (ISGs) that include genes important in host defense against viruses. Although some ISGs have been demonstrated to have antiviral functions, the antiviral activities of the majority of ISGs have not been confirmed. TREX1 (Three prime Repair EXonuclease1) is an exonuclease acting on ssDNA or mispaired 3’ termini. It has been associated with autoimmune diseases including Systemic Lupus Erythematosus and Aicardi-Goutieres Syndrome, which show over-expression of ISGs. TREX1 also facilitates HIV-1 infection by degrading cytosolic HIV-1 DNA, suggesting that HIV-1 may use TREX1 to escape host detection. The role of TREX1 in DC function is unknown. We have found that IFNα stimulates TREX1 expression in C57BL/6 bone marrow derived Dendritic Cells (myeloid DCs). TREX1 gene expression is induced within 1 h of IFNα treatment and continues to increase up to 6 h after stimulation, indicating that TREX1 is an early responsive ISG with sustained expression possibly due to autocrine IFNβ production. In addition, transcription of TREX1 by IFNα is impaired in myeloid DCs from Stat2-deficient mice, indicating that TREX1 expression is dependent on the canonical IFNAR/STAT2 signaling pathway. We are now studying TREX1 role in the antiviral response of DCs.