Dectin-1 epigenetic reprogramming rescues senescent-like Treg function in allergic asthma.

Abstract

Allergic asthma is characterized by immune dysregulation, and deficiencies in regulatory T-cell (Treg) function are a hallmark of the disease. However, mechanisms of Treg impairment for their therapeutic correction remain poorly defined. The results showed that patient Tregs exhibited a senescent phenotype, including shortened telomeres, increased SA-β-gal activity, and heightened apoptosis. Functionally, they were compromised, showing reduced suppressive capacity and a pro-inflammatory cytokine shift. KQS-1 treatment robustly reversed these defects, restoring FOXP3- and IL-10-dependent Treg suppressive capacity and the production of anti-inflammatory cytokines. This functional rescue centered on these two core Treg signature genes was dependent on Dectin-1 binding and a downstream Raf-1/ROS signaling axis, which drove a sustained epigenetic program characterized by increased H3K4me3 and H3K27ac at the FOXP3 and IL10 loci, focal hypomethylation, and chromatin remodeling at these specific loci. CRISPR-mediated deletion of Dectin-1 abrogated all beneficial effects of KQS-1. As proof of principle that KQS1 is protective, we demonstrate attenuation of airway hyperresponsiveness, inflammation, and remodeling in dust mite-sensitized mice and in recipient mice upon adoptive transfer of KQS-1-trained human Tregs.