Huysentruyt Jelle, Steels Wolf, Ruiz Pérez Mario, Verstraeten Bruno, Divert Tatyana, Flies Kayleigh, Lemeire Kelly, Takahashi Nozomi, De Bruyn Elke, Joossens Marie, Brown Andrew S, Lambrecht Bart N, Declercq Wim, Vanden Berghe Tom, Maelfait Jonathan, Vandenabeele Peter, Tougaard Peter
VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium.
Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
EMBO Rep. 2025 Apr 30. doi: 10.1038/s44319-025-00441-5.
RIPK1 is a crucial regulator of cell survival, inflammation and cell death. Human RIPK1 deficiency leads to early-onset intestinal inflammation and peripheral T cell imbalance, though its role in αβT cell-mediated intestinal homeostasis remains unclear. In this study, we demonstrate that mice with RIPK1 ablation in conventional αβT cells (Ripk1) developed a severe small intestinal pathology characterized by small intestinal elongation, crypt hyperplasia, and duodenum-specific villus atrophy. Using mixed bone marrow chimeras reveals a survival disadvantage of αβT cells compared to γδT cells in the small intestine. Broad-spectrum antibiotic treatment ameliorates crypt hyperplasia and prevents intestinal elongation, though villus atrophy persists. Conversely, crossing Ripk1 with TNF receptor 1 Tnfr1 knockout mice rescues villus atrophy but not intestinal elongation. Finally, combined ablation of Ripk1 and Casp8 fully rescues intestinal pathology, revealing that αβT cell apoptosis in Ripk1 drives the enteropathy. These findings demonstrate that RIPK1-mediated survival of αβT cells is essential for proximal small intestinal homeostasis. In Ripk1 mice, the imbalanced T cell compartment drives microbiome-mediated intestinal elongation and TNF-driven villus atrophy.
RIPK1是细胞存活、炎症和细胞死亡的关键调节因子。人类RIPK1缺乏会导致早发性肠道炎症和外周T细胞失衡，但其在αβT细胞介导的肠道内环境稳态中的作用仍不清楚。在本研究中，我们证明在传统αβT细胞中敲除RIPK1的小鼠（Ripk1）出现了严重的小肠病理改变，其特征为小肠延长、隐窝增生以及十二指肠特异性绒毛萎缩。使用混合骨髓嵌合体显示，在小肠中αβT细胞与γδT细胞相比存在生存劣势。广谱抗生素治疗可改善隐窝增生并防止小肠延长，尽管绒毛萎缩仍然存在。相反，将Ripk1与肿瘤坏死因子受体1（Tnfr1）基因敲除小鼠杂交可挽救绒毛萎缩，但不能挽救小肠延长。最后，联合敲除Ripk1和Casp8可完全挽救肠道病理改变，表明Ripk1中αβT细胞凋亡驱动了肠道病变。这些发现表明，RIPK1介导的αβT细胞存活对近端小肠内环境稳态至关重要。在Ripk1小鼠中，失衡的T细胞区室驱动微生物群介导的小肠延长和肿瘤坏死因子驱动的绒毛萎缩。
