Dissecting PGE₂-driven inhibition of T cell activation using single-cell multi-omic and inflammatory bowel disease...

Genetic and immunologic studies implicate the interleukin (IL)-23/T helper (Th)17 pathway in inflammatory bowel disease (IBD). IL-23 and IL-1β drive human Th17 differentiation, while prostaglandin E2 (PGE₂) and transforming growth factor-β (TGF-β) further modulate Th17 development and plasticity. However, how these inflammatory mediators influence human T cell regulatory programs remains incompletely understood. We used single-cell multi-omics to profile 171,829 peripheral blood T cells from 25 healthy donors in 64 samples exposed to activation stimuli, IL-1β and IL-23 alone or in combination with PGE₂, TGF-β, or both. PGE₂ broadly suppressed T cell activation, except in Th17 and T follicular helper cells, and markedly altered chromatin accessibility and gene expression, particularly in Th17, Th1, and regulatory T cells, where IBD-associated SNPs were enriched in open chromatin and connected to cell type-specific cis-regulatory elements. Our study demonstrates the utility of single-cell multi-omics for defining stimulus-specific effects on T cells and prioritizing disease-associated genes.