Abstract
BACKGROUND & AIMS: TOB1 is an anti-proliferative protein of Tob/BTG family and typically involved in the tumorigenesis and T cell activation. Although TOB1 is associated with T helper 17 cell-related autoimmunity, its role in modulating T cell-mediated immune responses in IBD remains poorly understood. Here, we explored its expression and the underlying mechanisms involved in the pathogenesis of inflammatory bowel disease (IBD). METHODS: TOB1 and ID2 expression in IBD patients was examined by quantitative real time polymerase chain reaction and immunohistochemistry. IBD CD4(+) T cells were transfected with lentivirus expressing TOB1, ID2, TOB1 short hairpin RNA and ID2 short hairpin RNA, respectively, and Tob1(-/-)CD4(+) T cells were transfected with lentivirus expressing Id2. Experimental colitis was established in Tob1(-/-) mice by trinitrobenzene sulfonic acid enema and in Rag1(-/-) mice reconstituted with Tob1(-/-)CD45RB(high)CD4(+) T cells to further explore the role of Tob1 in intestinal mucosal inflammation. Splenic CD4(+) T cells of Tob1(-/-) mice were sorted to determine transcriptome differences by RNA sequencing. RESULTS: TOB1 expression was decreased in inflamed mucosa and peripheral blood CD4(+) T cells of IBD patients compared with healthy subjects. Overexpression of TOB1 downregulated IBD CD4(+) T cells to differentiate into Th1/Th17 cells compared with control subjects. Severe colitis was observed in Tob1(-/-) mice through trinitrobenzene sulfonic acid enema or in Rag1(-/-) mice reconstituted with Tob1(-/-)CD45RB(high)CD4(+) T cells, compared with control animals. RNA sequencing analysis revealed ID2 as functional target of TOB1 to inhibit IBD CD4(+) T cell differentiation into Th1/Th17 cells. Mechanistically, TOB1 was associated with Smad4/5 to induce ID2 expression and restrain Th1/Th17 cell differentiation. CONCLUSIONS: TOB1 restrains intestinal mucosal inflammation through suppressing Th1/Th17 cell-mediated immune responses via the Smad4/5-ID2 pathway. It may serve as a novel therapeutic target for treatment of human IBD.