EQ504: A Novel AhR Agonist That Promotes Immune Tolerance Through Modulating T Cell Function 4678

Description Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that promotes immune tolerance at least in part by increasing the generation and function of regulatory T cells1. Efforts to target AhR have been hampered by the lack of drug candidates with good drug-like properties. Here we test the impact of a new small molecule AhR agonist EQ504, a derivative of the endogenous ligand ITE (2-(1’H-indole-3’-carbonyl)-thiazole-4-carboxylic acid methyl ester)) with increased potency, on Tregs (anti-inflammatory) and Th17 (pro-inflammatory) cells. EQ504 was tested on endogenous Tregs and Th17 in human PBMCs and during generation of in vitro differentiated Tregs (iTregs) and Th17 cells. When incubated with anti-CD3/anti-CD28 stimulated PBMCs, EQ504 increased FOXP3 expression in endogenous Tregs by ∼2-fold; no phenotypic changes were detected in Th17 cells. EQ504 had a greater impact during differentiation. iTregs differentiated in the presence of EQ504 had greater expression of CD39 and TIGIT, as well as an increase in IL-10 and IL-22 cytokine release. Conversely, during Th17 differentiation, EQ504 significantly decreased expression of IL-17A and IL-17F while increasing the expression of IL-22, which plays a pivotal role in maintaining barrier function in tissues such as the gut and skin2. EQ504 drives potent Treg stability and function, highlighting AhR modulation as a transformative strategy to rebalance Teff/Treg ratios in immunoinflammatory diseases.