The impact of the transcription factor interferon regulatory factor 1 (IRF1) in modulating the B cell immune responses

Inflammatory bowel disease (IBD), represented by Crohn’s disease (CD) and ulcerative colitis (UC), is a globally prevalent chronic gastrointestinal disease. IBD can be caused by an interaction of genetic predisposition, environmental factors and intestinal microbiome. As the etiology of IBD is not well understood, bacterial infections are also thought to influence and contribute to the development of IBD in predisposed individuals. Intensive research is focusing on identifying susceptibility loci and the inflammatory phenotype of immune cells in IBD. Among the IBD loci, transcription factors such as interferon regulatory factor 1 (IRF1) and T-box transcription factor (T-bet) have been shown to be relevant in patients with CD. IRF1 is known to be a regulator of defense gene expression and is upregulated in response to viral and bacterial infections. In addition, IRF1 is expressed in B cells with an IFN signature, which have a pro-inflammatory effect. Although B cells were not thought to be important in the pathogenesis of IBD, recent research brings light into the presence of pro-inflammatory B cells in the inflamed intestine. Furthermore, increased levels of IL-12/IL-23 and plasmablast/plasma cell infiltration in the intestine, as well as increased levels of IgA and IgG antibodies, have been described in IBD patients. In this study, my aim was to identify the role of IRF1 in B cell development and function to gain a better understanding of the susceptibility factors for the occurrence of chronic intestinal inflammation such as IBD. The results from RNA sequencing showed that the majority of differentially regulated genes in IRF1 deficient B cells belong to pathways involved in metabolism, interferon signature and immune response to bacterial molecules. Additionally, by deleting IRF1 in B cells expressing CD23 I demonstrated that the reduction of marginal zone (MZ) B cells in conditional knockout mice is IRF1-B cells intrinsic. I was also able to show that IRF1-deficient MZ B cells have a defect in the production of IL-10. IRF1 causes a downregulation of IL-12rb1 in B cells and MZ B cells, rendering them unresponsive to IL-12 signaling and impairing their ability to upregulate IL-10 production. I used T cell-independent, T cell-dependent immunization and Salmonella thyphimurium intestinal infection several models to investigate the role of IRF1 in in the immune response. The results showed that IRF1 is, at first sight, dispensable for the establishment of an efficient response due to the lack of effects on plasma cells specific antibody production. However, in each of the models, I observed a reduction in the plasmablast and a reduction in the total antibody response. Therefore, IRF1 could be an important factor in the regulation of IL-10 in B-cells, as well as the B-cell response to IL-12 and plasmablast differentiation. This may have a critical impact on prolonged inflammation in the intestine, such as that seen in inflammatory bowel disease.