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<p>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 (<i>Ripk1</i><sup><i>ΔCD4</i></sup>) 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 <i>Ripk1</i><sup><i>ΔCD4</i></sup> with TNF receptor 1 <i>Tnfr1</i><sup><i>−/−</i></sup> knockout mice rescues villus atrophy but not intestinal elongation. Finally, combined ablation of <i>Ripk1</i><sup><i>∆CD4</i></sup> and <i>Casp8</i><sup><i>∆CD4</i></sup> fully rescues intestinal pathology, revealing that αβT cell apoptosis in <i>Ripk1</i><sup><i>∆CD4</i></sup> drives the enteropathy. These findings demonstrate that RIPK1-mediated survival of αβT cells is essential for proximal small intestinal homeostasis. In <i>Ripk1</i><sup><i>∆CD4</i></sup> mice, the imbalanced T cell compartment drives microbiome-mediated intestinal elongation and TNF-driven villus atrophy.</p>

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RIPK1 ablation in T cells results in spontaneous enteropathy and TNF-driven villus atrophy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月30日

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  • Jelle Huysentruyt,
  • Wolf Steels,
  • Mario Ruiz Pérez,
  • Bruno Verstraeten,
  • Tatyana Divert,
  • Kayleigh Flies,
  • Kelly Lemeire,
  • Nozomi Takahashi,
  • Elke De Bruyn,
  • Marie Joossens,
  • Andrew S Brown,
  • Bart N Lambrecht,
  • Wim Declercq,
  • Tom Vanden Berghe,
  • Jonathan Maelfait,
  • Peter Vandenabeele,
  • Peter Tougaard

摘要

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 (Ripk1ΔCD4) 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 Ripk1ΔCD4 with TNF receptor 1 Tnfr1−/− knockout mice rescues villus atrophy but not intestinal elongation. Finally, combined ablation of Ripk1∆CD4 and Casp8∆CD4 fully rescues intestinal pathology, revealing that αβT cell apoptosis in Ripk1∆CD4 drives the enteropathy. These findings demonstrate that RIPK1-mediated survival of αβT cells is essential for proximal small intestinal homeostasis. In Ripk1∆CD4 mice, the imbalanced T cell compartment drives microbiome-mediated intestinal elongation and TNF-driven villus atrophy.