Downregulated Aryl Hydrocarbon Receptor Expression Is Linked with Increased IFN-γ Production and Impaired Immune Checkpoint Upregulation in Vitiligo.

Abstract

The kynurenine-aryl hydrocarbon receptor (AhR) axis restrains cytotoxic T-cell activity by tempering IFN-γ release and sustaining immune checkpoint expression, yet its status in vitiligo remains undefined. We profiled AhR expression in circulating T cells, quantified serum tryptophan and kynurenine, and assessed intracellular IFN-γ/IL-17A with soluble checkpoint molecules in 186 patients with nonsegmental vitiligo and 56 matched controls. Patients with vitiligo showed significantly reduced AhR expression in CD8⁺ T cells (P = .003) and a higher kynurenine/tryptophan ratio in active than in stable disease (P = .048). Low AhR expression in CD8⁺ T cells correlated inversely with IFN-γ-producing CD8⁺ cells (r = -0.376; P < .001), this correlation being stronger in active disease (r = -0.561). AhR expression positively correlated with soluble BTLA, soluble PD-1, and soluble TIM-3 levels in PBMC supernatants from patients with vitiligo. Pharmacologic activation of AhR with tapinarof dose-dependently suppressed IFN-γ⁺ T-cell frequencies, achieving a 55% reduction at 1 μM and a 47% reduction at 3 μM compared with stimulated controls (P < .05). These data identify disrupted kynurenine-AhR signaling as a driver of enhanced IFN-γ production in vitiligo and point to the potential of AhR agonists as targeted therapies to restore immune homeostasis and prevent disease activity in vitiligo.