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TOB1 Blocks Intestinal Mucosal Inflammation Through Inducing ID2-Mediated Suppression of Th1/Th17 Cell Immune Responses in IBD

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 unde...

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Detalles Bibliográficos
Autores principales: Lin, Ritian, Ma, Caiyun, Fang, Leilei, Xu, Chunjin, Zhang, Cui, Wu, Xiaohan, Wu, Wei, Zhu, Ruixin, Cong, Yingzi, Liu, Zhanju
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8881672/
https://www.ncbi.nlm.nih.gov/pubmed/34920145
http://dx.doi.org/10.1016/j.jcmgh.2021.12.007
Descripción
Sumario: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.