# AhR ligands in epigenetic dysregulation of T cells

> **NIH NIH R01** · UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA · 2021 · $435,108

## Abstract

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.

## Key facts

- **NIH application ID:** 10086946
- **Project number:** 5R01AI123947-05
- **Recipient organization:** UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
- **Principal Investigator:** Mitzi Nagarkatti
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $435,108
- **Award type:** 5
- **Project period:** 2017-02-10 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10086946

## Citation

> US National Institutes of Health, RePORTER application 10086946, AhR ligands in epigenetic dysregulation of T cells (5R01AI123947-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10086946. Licensed CC0.

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