Restoring Balance: RIPK1 inhibitor counteracts TL1A-induced T cell responses 2199

Abstract Description Elevated levels of TL1A and IL-9 correlate with increased severity of inflammatory bowel disease. Th9 cells interact with TL1A, produce IL-9, and participate in IBD development; however, their specific role in IBD remain unclear. This study investigated TL1A/DR3 signaling in human Th9 cells and assessed the impact of a RIPK1 inhibitor on this pathway. TL1A-stimulated Th9 cells exhibit a pro-inflammatory profile compared to control Th9 conditions. Blocking TL1A/DR3 signaling using a RIPK1 inhibitor decreased the pro-inflammatory markers triggered by TL1A, shown by reduced levels of IL-9 and IL-13. scRNA-seq revealed that TL1A stimulation activates inflammatory pathways in Th9 cells, and the RIPK1 inhibitor mitigates these pro-inflammatory signatures. Mechanistically, ChIP-qPCR demonstrated that RIPK1 inhibitor reduced transcription factor binding to promoter and enhancer regions on the human Il9 loci. Within a T cell adoptive transfer model, it was observed that Th9 cells markedly increased pro-inflammatory Th1 and Th17 cell responses, signifying a key function of IL-9 signaling in contributing to intestinal inflammation. We describe herein that a functional DR3 receptor can regulate Th9 cell pathogenicity, thus, constituting a mechanism by which TL1A/DR3 signaling mediates intestinal inflammation. Targeting the TL1A/DR3/Th9 pro-inflammatory pathway could serve as a potential therapeutic approach for individuals with inflammatory bowel disease. Funding Sources Supported by Eli Lilly & Company Topic Categories Therapeutic Approaches to Autoimmunity (THER)