The role of interferon-regulated genes in the immune system

Abstract

Type I interferons (IFNs) are potent inducers of the first-line defense against pathogens. Their activity leads to the up- and downregulation of a large number of genes with various effects on the immune system, including direct effects on the pathogens. Due to the strong response evoked by IFN signaling, the IFN pathway is tightly regulated by IFN stimulated genes to avoid detrimental effects of long-term exposure. If the IFN signaling pathway is not regulated properly, or for other reasons constantly activated, it can lead to interferonopathies and autoimmune diseases such as systemic lupus erythematosus (SLE) and Sjögren’s syndrome (SS). Indeed, many therapeutics targeting the IFN pathway are currently in clinical trials. In contrast, type I IFNs are used to treat certain types of cancer, virus infections and multiple sclerosis. The complex role of type I IFN signaling in disease is not well understood and need further characterization for better therapeutic inventions.

The aim of this thesis was to identify genes that are regulated by type I IFNs and investigate their role in the immune system. To do this, we quantified the expression of interferon-regulated genes in sorted immune cells from patients with primary SS, and from individuals treated with IFN b. Using global gene expression analysis on PBMCs as well as qPCR on sorted cells, we could identify several 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 upregulated in T cells, monocytes and neutrophils and miR-150-5p that was selectively downregulated in monocytes. The downregulated expression of miR-150-5p consequently led to an increased expression of its target c-Myb. In addition, monocytes from patients with SLE displayed an increase in c-Myb target genes.

When investigating the regulation of BAFF and TRIM21, we found that both were regulated by members of the interferon regulatory factor (IRF) family. Specifically, both were upregulated by IRF1 and IRF2, and downregulated by IRF4 and IRF8. To further investigate the role of TRIM21 in the immune system, we generated Trim21-/- mice. These mice were prone to granulocyte infiltrations and developed symptoms of autoimmune disease after being triggered by metal ear tags. We found that TRIM21 negatively regulates the immune response by ubiquitinating IRFs, and that naïve Trim21-/- mice control the development of eosinophils in the bone marrow.