The TL1A/DR3 signaling pathway plays a critical role in driving Crohn’s disease-like intestinal inflammation by regulating the formation and pathogenicity of Th9 cells. Th9 cells, a subset of T helper cells, produce the proinflammatory cytokine IL9, which is central to the inflammatory processes in Crohn’s disease.
The TL1A/DR3 signaling pathway plays a critical role in driving Crohn’s disease-like intestinal inflammation by regulating the formation and pathogenicity of Th9 cells. Th9 cells, a subset of T helper cells, produce the proinflammatory cytokine IL9, which is central to the inflammatory processes in Crohn’s disease. Functional DR3 signaling enhances the inflammatory capacity of Th9 cells, while its absence shifts Th9 cells toward a regulatory phenotype, reducing inflammation. DR3-deficient Th9 cells exhibit downregulation of proinflammatory genes (e.g., Spi1, Batf3) and upregulation of regulatory genes (e.g., Il10, Foxp3), promoting immune tolerance.
DR3 activation engages key pathways such as JAK–STAT, PI3K–AKT, and TCR signaling, amplifying cytokine production and pathogenic T-cell function. Additionally, DR3 signaling inhibits the Hippo–YAP/TAZ pathway, impairing epithelial repair and favoring chronic inflammation. It also polarizes macrophages toward a proinflammatory M1 phenotype, exacerbating tissue damage.
In Crohn’s-like ileitis models (e.g., SAMP1/YitFc mice), adoptive transfer of Th9 cells with functional DR3 (Th9WT) caused severe intestinal inflammation, while DR3-deficient Th9 cells (Th9KO) led to minimal inflammation. Blocking IL9 in these models significantly reduced inflammation, highlighting its therapeutic potential.
Human studies confirm the relevance of this pathway, with elevated levels of IL9, SPI1, BATF3, and STAT6 observed in Crohn’s and ulcerative colitis patients. The TL1A/DR3/Th9 axis represents a novel immune mechanism driving chronic intestinal inflammation and fibrosis. Targeting DR3 or IL9 signaling offers a promising therapeutic strategy to restore immune balance and treat Crohn’s disease.
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