Deciphering the role of the IRF4 interactome in differentiating regulatory T and T helper 17 cells in health and autoimmune disease

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While T helper (Th) 17 cells have been implicated in the initiation and progression of autoimmune diseases, CD4+FOXP3+ regulatory T (Treg) cells have been shown to crucially contribute to the maintenance of peripheral tolerance by preventing these autoaggressive immune responses. It has been shown, that the transcription factor IRF4 plays a key role in Th17 and Treg cell lineage determination. The protein kinase CK2 is involved in the IRF4-steered regulation of gene transcription and CK2 activity essentially contributes to the delicate equilibrium between Th17 and Treg cells. Moreover, data indicate that IRF4 executes different tasks acting either as homodimer or in concert with different partners at certain stages during the course of T cell differentiation. However, there is still little knowledge about the underlying mechanisms and binding partners of IRF4 at distinct time points during the differentiation process. Further, it still remains elusive to which extent the events induced by IRF4 and its binding partners explain the pivotal role of this transcription factor in functionally opposed T cell subsets like Treg cells and Th17 cells.One of the major goals of the present grant application is to shed light on the impact of CK2 and IRF4 on Th17 and Treg cell lineage determination. Towards this purpose we will integrate time-resolved interactome, ChIPSeq, transcriptome and proteome analyses in the above-mentioned T cell subsets for the identification of CK2-dependent and CK2-independent IRF4 protein and DNA targets. The time-resolved multi"omics" dataset will be generated using Th17 and Treg cells generated ex vivo from transgenic reporter mice. The data resource created in the proposed project will allow us to pick candidate genes and proteins interacting with IRF4 and elucidate their impact on Th17 and Treg cell lineage determination in the preclinical model of multiple sclerosis, named experimental autoimmune encephalomyelitis (EAE).