Tumor Necrosis Factor-Like Ligand 1A/Death Receptor 3 Signaling Regulates the Generation of Pathogenic T Helper 9...

Death receptor 3 (DR3) and its ligand, tumor necrosis factor-like ligand 1A (TL1A), regulate the balance between effector and regulatory T cells in inflammatory bowel disease (IBD). Although interleukin 9 (IL9)-secreting T helper 9 (Th9) cells are linked to ulcerative colitis, their role in Crohn's disease (CD) is unclear. We investigated the role of DR3 signaling in Th9 cell differentiation in mouse models of CD-like ileitis and colitis.

Polarized Th9 cells with functional DR3 and DR3-deficient Th9 cells from SAMP wild-type (Th9_WT) and DR3^-/-×SAMP knockout (Th9_KO) mice, respectively, were characterized and adoptively transferred into Rag2^-/- and SAMP×Rag2^-/- recipients. Expression of Th9-associated molecules from experimental mice and IBD patients/controls was compared.

Th9_WT possess a proinflammatory profile compared with Th9_KO cells; conversely, ablation of DR3 signaling generates anti-inflammatory responses, as reflected by increased IL10-producing cells in DR3^-/-×SAMP mice. RNA sequencing and phosphoproteomic analyses show that inflammatory pathways are robustly activated in Th9_WT compared with Th9_KO cells, whereas Th9 cells are detected in SAMP mice in vivo, and Th9-related genes display the same expression patterns in both experimental ileitis and IBD patients. Finally, in the T-cell adoptive transfer model, Th9_KO cells are less colitogenic than Th9_WT, whereas IL9 blockade diminishes the severity of intestinal inflammation, indicating a crucial role of functional DR3 receptor in the pathogenicity of Th9 cells.

We demonstrate that the functional DR3 receptor is essential for Th9 cell pathogenicity, revealing a new mechanism by which TL1A/DR3 signaling drives experimental CD-like ileitis. The TL1A/DR3/Th9 proinflammatory pathway may offer a novel therapeutic target for patients with CD.