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

## TL;DR

Removing RIPK1 in T cells causes intestinal disease in mice, showing its importance for gut health and T cell survival.

## Contribution

Shows that RIPK1 is essential for αβT cell survival and intestinal homeostasis in mice.

## Key findings

- RIPK1 ablation in αβT cells causes small intestinal pathology including villus atrophy and elongation.
- TNF signaling drives villus atrophy, while the microbiome contributes to intestinal elongation.
- Combined RIPK1 and Casp8 ablation rescues intestinal pathology, showing apoptosis is central to the disease.

## Abstract

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.

Ablation of RIPK1 in αβT cells results in spontaneous proximal small intestinal pathology, characterized by microbiome-mediated epithelial hyperproliferation and TNF-driven villus atrophy, underlining the critical role of RIPK1 in intestinal homeostasis.

Ripk1ΔCD4 mice develop spontaneous enteropathy mimicking small intestinal pathology in human RIPK1 deficiency.The enteropathy in Ripk1ΔCD4 mice is driven by enhanced caspase-8-mediated αβT cell apoptosis.This αβT cell apoptosis is associated with increased TNF + γδT cells and reduced IL-10 + CD4 T cells.The microbiome contributes to small intestinal elongation, while TNF drives the villus atrophy through TNFR1.

Ripk1ΔCD4 mice develop spontaneous enteropathy mimicking small intestinal pathology in human RIPK1 deficiency.

The enteropathy in Ripk1ΔCD4 mice is driven by enhanced caspase-8-mediated αβT cell apoptosis.

This αβT cell apoptosis is associated with increased TNF + γδT cells and reduced IL-10 + CD4 T cells.

The microbiome contributes to small intestinal elongation, while TNF drives the villus atrophy through TNFR1.

Ablation of RIPK1 in αβT cells results in spontaneous proximal small intestinal pathology, characterized by microbiome-mediated epithelial hyperproliferation and TNF-driven villus atrophy, underlining the critical role of RIPK1 in intestinal homeostasis.