AhR ligands in epigenetic dysregulation of T cells

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AhR is a cytosolic transcription factor that can be activated by wide range of chemicals including environmental contaminants, such as 2,3,7,8-Tetrachlorodibenzodioxin (TCDD), which leads to metabolism and regulation of toxic effects. AhR can also be activated by endogenous ligands and dietary compounds. Recent groundbreaking studies demonstrated that AhR activation can also regulate T cell differentiation, specifically the differentiation of Foxp3+ regulatory T cells (T regs) and proinflammatory Th17 cells that play a role in extracellular infections and autoimmune diseases such as multiple sclerosis (MS). Interestingly, AhR ligands were shown to have contrasting effects on Treg/Th17 differentiation, the reasons for which are not clear. For example, studies, including ours, demonstrated that some AhR ligands, such as TCDD, promoted the differentiation of Tregs while dampening that of Th17 cells, while a tryptophan photoproduct, 6-formylindolo[3,2-b]carbazole (FICZ), exerted contrasting effects. We have generated exciting preliminary data indicating that AhR activation triggers dysregulation in the microRNA (miR) expression and other epigenetic pathways. Based on the above, we will test the hypothesis that AhR-ligand complex may interact with dioxin response elements (DREs) on gene promoters of microRNAs as well as induce other epigenetic pathways, which together alter the expression of the miRs, which in turn, regulate the differentiation of encephalitogenic T cells. We will test our hypothesis using an experimental model of MS called Experimental Autoimmune Encephalomyelitis (EAE). In Aim1, we will test whether TCDD and FICZ induce unique miR expression profiles in purified Tregs/Th17 cells. Based on our preliminary data, we will focus on miR31-5p and miR1192 that target the expression of FoxP3 and IL-17. Specifically, we will examine whether the interactions of AhR-ligand complex with the DREs on these miR gene promoters are responsible for the disparate responses. In Aim 2, we will test whether the contrasting effect of TCDD and FICZ is due to differential DNA methylation/hydroxymethylation of these miR gene promoters as well as due to histone modifications. In Aim 3, we will determine whether miR mimics or antagomirs as well as pharmacological intervention of DNA methylation/hydroxymethylation and histone modification would reverse the inflammatory response and clinical outcome following ligation AhR with TCDD or FICZ. The proposed studies are highly significant in that we will identify novel epigenetic pathways triggered by AhR activation leading to immune regulation. Our studies will also provide novel information on whether targeting such epigenetic pathways in vivo can prevent and treat inflammatory and autoimmune diseases.