Dokument

Summary:
Interferon regulatory factor 4 is a crucial factor in adaptive immunity in both T and B cell mediated processes. Knockout mice lacking IRF4 show severe defects in developing functional T cell subsets, including Th2, Th9 and Th17, as well as B cells arrested in early development stages, which leads to absence of IgM in the serum. In T cells, IRF4 serves as an initiation factor conveying TCR signals, priming cells for proliferation and inducing master transcriptional regulators such as GATA3, T-bet and RORγt. To fulfil this central role, interaction with several partners is required, among them BATF and PU.1. We hypothesize that through precise alterations in IRF4, its functionality can be altered to achieve selective modification of its immunoregulatory effects. Based on literature results from binding assays, structural analysis and recurring mutations in cancer patients, we tested many point mutations in IRF4 for their functionality in Th2, Th9 and Th17 differentiation. Several mutations show immunomodulatory potential. Most prominent among them is L116R, which induces Th9 differentiation and IL-9 production in Th2 cells, while at the same time reducing Th2 and Th17 differentiation. Further, we could show that autoinhibition of IRF4 is differentially affecting helper T cell subtypes, acting much stronger on Th9 and Th17 cells compared to Th2 differentiated cells. In addition, tumors emerging in old IRF4 knockout mice allowed us to further study leukemogenesis and B cell development in the context of IRF4 deficiency, leading to a disease similar to human Ph-like B-ALL. Treatment of this disease with the JAK inhibitor Ruxolitinib increased survival by reducing blast infiltration in the central nervous system and solid organs. Here we show that immunomodulation via point mutations is possible and that IRF4 has subdomains that differentially affect helper T cell subtypes, further scrutinize the effects of autoinhibition in IRF4 and establish a potential mouse model for human Ph-like B-ALL.

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