Type I interferons (IFNs) are potent inducers of the first-line defense against pathogens. Theiractivity leads to the up- and downregulation of a large number of genes with various effects on theimmune system, including direct effects on the pathogens. Due to the strong response evoked byIFN signaling, the IFN pathway is tightly regulated by IFN stimulated genes to avoid detrimentaleffects of long-term exposure. If the IFN signaling pathway is not regulated properly, or for otherreasons constantly activated, it can lead to interferonopathies and autoimmune diseases such assystemic lupus erythematosus (SLE) and Sjögren’s syndrome (SS). Indeed, many therapeuticstargeting the IFN pathway are currently in clinical trials. In contrast, type I IFNs are used to treatcertain types of cancer, virus infections and multiple sclerosis. The complex role of type I IFNsignaling in disease is not well understood and need further characterization for better therapeuticinventions.The aim of this thesis was to identify genes that are regulated by type I IFNs and investigate theirrole in the immune system. To do this, we quantified the expression of interferon-regulated genesin sorted immune cells from patients with primary SS, and from individuals treated with IFNβ.Using global gene expression analysis on PBMCs as well as qPCR on sorted cells, we could identifyseveral genes that were differentially regulated by type I IFNs in different immune cell populations.Among them were TRIM21 that was upregulated in T cells and B cells, BAFF that was upregulatedin T cells, monocytes and neutrophils and miR-150-5p that was selectively downregulated inmonocytes. The downregulated expression of miR-150-5p consequently led to an increasedexpression of its target c-Myb. In addition, monocytes from patients with SLE displayed an increasein c-Myb target genes. When investigating the regulation of BAFF and TRIM21, we found thatboth were regulated by members of the interferon regulatory factor (IRF) family. Specifically, bothwere upregulated by IRF1 and IRF2, and downregulated by IRF4 and IRF8. To further investigatethe role of TRIM21 in the immune system, we generated Trim21-/- mice. These mice were prone togranulocyte infiltrations and developed symptoms of autoimmune disease after being triggered bymetal ear tags. We found that TRIM21 negatively regulates the immune response by ubiquitinatingIRFs, and that naïve Trim21-/- mice control the development of eosinophils in the bone marrow.