Skip to main content

This is a preprint.

It has not yet been peer reviewed by a journal.

The National Library of Medicine is running a pilot to include preprints that result from research funded by NIH in PMC and PubMed.

bioRxiv logoLink to bioRxiv
[Preprint]. 2024 Feb 12:2024.02.09.579684. [Version 1] doi: 10.1101/2024.02.09.579684

TL1A/DR3 signaling regulates the generation of pathogenic Th9 cells in experimental inflammatory bowel disease

Paola Menghini, Ludovica Butto, Adrian Gomez-Nguyen, Natalia Aladyshkina, Kristine-Ann Buela, Abdullah Osme, Ricky Chan, Giorgos Bamias, Theresa T Pizarro, Fabio Cominelli
PMCID: PMC10888761  PMID: 38405912

Abstract

Objective: Death receptor 3 (DR3) and its ligand tumor necrosis factor like ligand 1A (TL1A), are involved in the regulation of the balance between effector and regulatory T cells in IBD. New evidence suggests a role of IL-9-secreting Th9 cells in the pathogenesis of ulcerative colitis (UC), although the molecular pathways through which IL-9 and Th9 cells may mediate intestinal inflammation in Crohn's disease (CD) are still unclear. Design: We investigated the role of DR3 signaling in the differentiation of Th9 cells in mouse models of CD-like ileitis and colitis, including SAMP1/YitFc (SAMP) mice. Results: Polarized-Th9 cells with functional DR3 from SAMP WT (Th9WT) harbor a pro-inflammatory signature compared to DR3-deficient Th9 cells that were obtained from DR3-/-xSAMP mice (Th9KO). Conversely, ablation of DR3 signaling generated anti-inflammatory responses, as reflected by higher numbers of IL-10 producing cells in DR3-/-xSAMP mice. Additionally, RNA-seq and phosphoproteomic analyses showed that inflammatory pathways are significantly more activated in Th9WT than in Th9KO cells. Finally, in the T-cell adoptive transfer model, Th9KO cells were less colitogenic than Th9WT, while IL-9 blockade diminished the severity of intestinal inflammation, indicating a crucial role of functional DR3 receptor in Th9 cells pathogenicity. Conclusion: We describe herein that a functional DR3 receptor is required for the pathogenicity of Th9 cells, thus, constituting a novel mechanism by which TL1A/DR3 signaling mediates experimental CD-like ileitis. The TL1A/DR3/Th9 pro-inflammatory pathway may offer a novel therapeutic target for patients with CD.

Full Text Availability

The license terms selected by the author(s) for this preprint version do not permit archiving in PMC. The full text is available from the preprint server.


Articles from bioRxiv are provided here courtesy of Cold Spring Harbor Laboratory Preprints

RESOURCES